Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes

ABSTRACT

The present invention relates to a melanin concentrating hormone antagonist compound of formula I: (I); or a pharmaceutically acceptable salt, solvate, enantiomer or prodrug thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and related diseases.

This is National filing under 35 U.S.C. § 371 of PCT/US03/1213, filedMay 6, 2003, which claims priority from U.S. Provisional Application No.60/380,351, filed May 13, 2002.

FIELD OF INVENTION

The present invention is in the field of medicine, particularly in thetreatment of obesity and diseases caused by or exacerbated by obesity.More specifically, the present invention relates to antagonists ofmelanin concentrating hormone useful in the prevention and treatment ofobesity and related diseases.

BACKGROUND OF THE INVENTION

The affluence of the 90's along with the exponential increase in foodproduction particularly in Western and Asian economies has resulted infeeding patterns that lead to obesity. Obesity is defined as beingexcessively overweight. Excessive weight is generally characterized byexcessive body fat, because unused energy is stored in the adiposetissues as fat.

Obesity has associated with it, economic and social costs. Obese people,an increasing proportion of developed and developing societies, areregarded as having out of control feeding habits often associated withlow self-esteem. Moreover, obese persons are more likely to have medicalproblems associated with or exacerbated by the excess body weight.Examples of medical conditions caused, exacerbated or triggered byexcessive weight include bone fractures, pains in the knee joints,arthritis, increased risk of hypertension, artherosclerosis, stroke,diabetes, etc.

BACKGROUND OF THE INVENTION

Melanin concentrating hormone (MCH) is a 19 amino acid neuropeptideproduced in the lateral hypothalamic area and zona incerta, althoughMCH-expressing neurons project to numerous regions of the brain. MCH isprocessed from a larger pre-prohormone that also includes a secondpeptide, NEI, and possibly a third, NGE (Nahon, Crit Rev inNeurobiology, 8:221–262, 1994). MCH mediates its effects through atleast two G protein-coupled receptors, MCHR1 and MCHR2 (Saito et al.Nature 400: 265–269, 1999; Hill et al., J Biol Chem 276: 20125–20129,2001). Both receptors are expressed in regions of the brain consistentwith MCH neuronal projection and known MCH physiologic function (Hervieuet al., Eur J Neuroscience 12: 1194–1216, 2000; Hill et al., J Biol Chem276: 20125–20129, 2001; Sailer et al., Proc Nat Acad Sci 98: 7564–7569,2001).

Extensive evidence exists to support the orexigenic activity of MCH. MCHmRNA is elevated in rodent models of obesity and in the fasted state (Quet al., Nature 380: 243–247, 1996). Intracerebroventricularlyadministered MCH increases feeding and blocks the anorexic effect ofα-melanocyte stimulating hormone (Ludwig et al., Am J Physiol 274:E627–E633, 1998). MCH knock-out mice (MCH^(−/−) mice) are lean,hypophagic and hypometabolic (Shimada et al., Nature 396: 670–674,1998), while MCH over-expressing transgenic mice are obese and insulinresistant (Ludwig et al., J Clin Invest 107: 379–386, 2001). MCHR1^(−/−)mice have recently been reported to be lean and hypermetabolic,indicating that the R1 isoform mediates at least some of the metaboliceffects of MCH (Marsh et al., Proc Nat Acad Sci 99: 3240–3245, 2002;Chen et al., Endocrinology, 2002, in press).

In addition to its effects on feeding, MCH has been implicated inregulation of the hypothalamic-pituitary-adrenal axis through modulationof CRF and ACTH release (Bluet-Pajot et al., J Neuroendocrinol 7:297–303, 1995). MCH may also play a role in the modulation ofreproductive function (Murray et al., J Neuroendocrinol 12: 217–223,2000) and memory (Monzon et al., Peptides 20: 1517–1519, 1999).

The current preferred treatment for obesity as well as Type IInon-insulin dependent diabetes is diet and exercise with a view towardweight reduction and improved insulin sensitivity for diabetics. Patientcompliance, however, is usually poor. The problem is compounded by thefact that there are currently only two medications approved for thetreatment of obesity (sibutramine, or Meridian and orlistat, orXenical™.

PCT application number WO 01/21577 (JP00/06375) filed Sep. 19, 2000,discloses compounds reportedly useful as antagonists of the MCHreceptor. In particular the WO 01/21577 application claims a compound offormula A

wherein:

-   Ar¹ is a cyclic group that may have substituents;-   X is a spacer having a main chain of 1 to 6 atoms;-   Y is a bond or a spacer having a main chain of 1 to 6 atoms;-   Ar is a monocyclic aromatic ring which may be condensed with a 4 to    8 membered non-aromatic ring, and may have further substituents;-   R¹ and R² are independently hydrogen atom or a hydrocarbon group    which may have substituents;-   R¹ and R² together with the adjacent nitrogen atom may form a    nitrogen-containing hetereo ring which may have Substituents; R² may    form a spiro ring together with Ar; or-   R², together with the adjacent nitrogen atom and Y, may form a    nitrogen-containing hetero ring which may have substituents; or    salts thereof.

PCT application number WO 01/82925, filed Apr. 26, 2001, also disclosescompounds reportedly useful as antagonists of the MCH receptor. Inparticular the WO 01/82925 application claims a compound of formula B

wherein:

-   Ar¹ is an optionally substituted cyclic group;-   X and Y are independently a spacer having a C₁₋₆ main chain;-   Ar is an optionally substituted fused polycyclic aromatic ring;-   R¹ and R² are independently hydrogen atom or an optionally    substituted hydrocarbon group; or alternatively R¹ and R² together    with the nitrogen atom adjacent thereto may form a nitrogenous    heterocycle, or R² together with the nitrogen atom adjacent thereto    and Y may form an optionally substituted nitrogenous heterocycle, or    R² together with the nitrogen atom adjacent thereto, Y, and Ar may    form a fused ring.

PCT application number WO 01/87834, filed May 15, 2001, also disclosescompounds reportedly useful as antagonists of the MCH receptor. Inparticular the WO 01/87834 application claims a compound of formula C.

Wherein;

-   R represents hydrogen, halogen, or an optionally substituted cyclic    group; X represents a bond or a spacer in which the main chain has    one to ten atoms; Y represents a spacer in which the main chain has    one to six atoms; ring A represents a benzene ring which may have    other substituents; ring B represents a five- to nine-membered    nitrogenous nonaromatic heterocycle which may have other    substituents; and R¹ and R² are the same or different and each    represents hydrogen, an optionally substituted hydrocarbon group, or    an optionally substituted heterocyclic group, or R¹ and R² may form    an optionally substituted nitrogenous heterocycle in cooperation    with the adjacent nitrogen atom and R² may form an optionally    substituted nitrogenous heterocycle in cooperation with the adjacent    nitrogen atom and Y.

Japanese patent application number JP2001-226269A also disclosescompounds reportedly useful as antagonists of the MCH receptor. Inparticular the JP2001-226269A application claims a compound of formulaD.

Wherein:

-   Ar is a substituted group-contg. arom. ring, X₁ is a substituted    group-contg. divalent main chain of 1–5 atoms, X₂, X₃ and X₄ are    linking arms, and R2 is a basic substituting group, and its salts.

Current treatments targeted at obesity have side effects. Examples ofsuch treatments include phen-phen, and various over-the-counter appetitesuppressants. These agents have not been proven effective for allpatients and for sustainable periods of time. Similarly, the approvedtreatments, sibutramine (Meridia™) and orlistat (Xenical™) have beenassociated with side effects which may compromise compliance and maypreclude long term use for sustained weight loss for certain patientpopulations.

Therefore, there is a need for new and/or improved therapeuticallyeffective agents useful as anatagonist of melanocortin releasing hormoneto better control the dietary habits, minimize the preponderance ofobesity and treat, prevent and/or ameliorate the effects of obesityincluding for example diabetes.

SUMMARY OF INVENTION

The present invention relates to a compound of formula I:Ar¹-L¹-Ar²—Ar³-L²-Q  (I)or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomeror mixture of diastereomers or prodrug thereof wherein:

-   Ar¹ is a cyclic group optionally substituted with one to five groups    selected from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy,    C₁–C₈ alkoxy, C₁–C₈ alkylaryl, phenyl, —O-aryl, heteroaryl,    cycloalkyl, C₁–C₈ alkylcycloalkyl, cyano, —(CH₂)_(n)NR¹⁶, C₁–C₈    haloalkyl, C₁–C₈ haloalkoxy, halo, (CH₂)_(n)COR⁶, (CH₂)_(n)NR⁵SO₂R⁶,    —(CH₂)_(n)C(O)NR⁶R⁶, heterocyclic, and C₁–C₈ alkylheterocyclic;    wherein the cycloalkyl, phenyl, aryl, and heterocyclic    susbstitutents are each optionally substituted with one to three    groups selected from hydroxy, C₁–C₈ alkoxyalkyl, C₁–C₈ haloalkoxy,    C₁–C₈ alkyl, halo, C₁–C₈ haloalkyl, nitro, cyano, amino,    carboxamido, phenyl, aryl, alkylheterocyclic, heterocyclic, and oxo;-   L¹ is a bond or a divalent linker having a main chain of 1 to 10    atoms; or represented by the formula X₂—(CR³R⁴)_(m)—X₃ where X₂ is    attached to Ar¹ and X₃ is attached to Ar² wherein R³ and R⁴ are    independently selected from a bond, hydrogen, C₁–C₈ alkyl, C₂–C₈    alkylene, C₂–C₈ alkynyl, phenyl, aryl, C₁–C₈ alkylaryl; wherein the    alkyl, alkenyl, phenyl, and aryl groups are optionally substituted    with one to five substitutents independently selected from oxo,    nitro, cyano, C₁–C₈ alkyl, aryl, halo, hydroxy, C₁–C₈ alkoxy, C₁–C₈    halaoalkyl, (CH₂)_(n)C(O)R⁶, and (CH₂)_(n)CONR⁶R⁶;-   X₂ is independently oxygen, —CH, —CONH(CR³R⁴)_(m), —NHCO(CR³R⁴)_(m),    —(CR³R⁴)_(m), —CHR⁶, —NR⁵, S, SO, SO₂, —O(CR³R⁴)_(m), or    —S(CR³R⁴)_(m);-   X₃ is independently oxygen, —C, —CH, —CHR⁶, —(CR³R⁴)_(m),    —CONH(CR³R⁴)_(m), —NHCO(CR³R⁴)_(m), —NR⁵, —NR⁵(CR³R⁴)_(m), S,    SO(CR³R⁴)_(m), SO₂(CR³R⁴)_(m), S(CR³R⁴)_(m), SO, or SO₂;    —O(CR³R⁴)_(m), or —S(CR³R⁴)_(m);-   AR² is a 5-member monocyclic heterocyclic aromatic group or    positional isomer thereof, having 1, 2, or 3 heteroatoms    independently selected from nitrogen, oxygen and sulfur; and    optionally substituted with one to three substitutents selected from    C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy, C₁–C₈ alkoxy,    C₁–C₈ alkylaryl, phenyl, aryl, C₃–C₈ cycloalkyl, C₁–C₈    alkylcycloalkyl, cyano, C₁–C₈ haloalkyl, halo, (CH₂)_(n)C(O)R⁶,    (CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR⁶R⁶, and C₁–C₈    alkylheterocyclic;-   AR³ is a 6-member monocyclic, aromatic, carbocyclic or heterocyclic    ring having 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen    and sulfur and which is optionally substituted with one to three    substituents independently selected from C₁–C₈ alkyl, C₂–C₈ alkenyl,    C₂–C₈ alkynyl, halo, —NWR⁵, C₁–C₈ haloalkyl, C₃–C₈ cycloalkyl,    hydroxy, alkoxy, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶,    (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR⁶R⁶, phenyl, C₁–C₈ alkylaryl, and    aryl;-   L² is a divalent linker having a chain length of between 1 and 10    atoms in the main chain or is represented by the formula:    X₄—(CR³R⁴)_(m)—X₅;-   wherein X₄ is attached to AR³ and is selected from the group    consisting of C, —CH, CHR⁶, —CO, O, —NR⁵, —NC(O)—, —NC(S),    —C(O)NR⁵—, —N^(6′)C(O)NR⁶, —NR^(6′)C(S)NR⁶, —SO₂NR⁷, —NRSO₂R⁷, and    —NR⁶OC(NR⁵)NR⁶;-   X₅ is selected from the group consisting of —CH₂, —CH,    —O(CR³R⁴)_(m), NR³(CR³R⁴)_(m), SO, SO₂, S, and SCH₂; wherein the    group X₄—(CR³R⁴)_(m)—X₅ imparts stability to the compound of    formula (1) and may be a saturated or unsaturated chain or divalent    linker.-   Q is a basic group or a group represented by —NR¹R²; wherein-   R¹ and R² are independently hydrogen, C₁–C₈ alkyl, C₂–C₈ alkenyl,    C₃–C₈ cycloalkane, C₁–C₈ alkylaryl, —C(O)C₁–C₈ alkyl, —C(O)OC₁–C₈    alkyl, C₁–C₈ alkylcycloalkane, (CH₂)_(n)C(O)OR⁵, (CH₂)_(n)C(O)R⁵,    (CH₂)_(n)C(O)NR⁶, and (CH₂)_(n)NSO₂R⁵; wherein each of the alkyl,    alkenyl, aryl are each optionally substituted with one to five    groups independently selected from C₁–C₈ alkyl, C₂–C₈ alkenyl,    phenyl, and alkylaryl; and-   wherein R¹ and R² may combine together, and with the nitrogen atom    to which they are attached or with 0, 1, 2 or 3 atoms adjacent to    the nitrogen atom to form a nitrogen containing heterocycle which    may have 1, or 2 substituents independently selected from C₁–C₈    alkyl, C₂–C₈ alkenyl, C₃–C₈ cycloalkane, C₁–C₈ alkylaryl, —C(O)C₁–C₈    alkyl, —C(O)OC₁–C₈ alkyl, C₁–C₈ alkylcycloalkane, oxo, halo amino,    and (CH₂)_(n)C(O)NR⁶R⁶;-   provided that L²-Q is not CONH₂; wherein R¹ and R² may combine with    the nitrogen atom to which they are attached to form and imine; and    provided that Q is not a subsituent on an amide;-   R⁵ is hydrogen, CN, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₅–C₈ alkylaryl,    (CH₂)_(n)NSO₂C₁–C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,    —C(O)C₁–C₈ alkyl, or —C(O)OC₁–C₈ alkyl; and-   R⁶ and R^(6′) are each independently hydrogen, C₁–C₈ alkyl, phenyl,    aryl, C₁–C₈alkylaryl, or C₃–C₈cycloalkyl;-   R⁷ is hydrogen, C₁–C₈ alkyl, phenyl, aryl, C₁–C₈alkylaryl, or    C₃–C₈cycloalkyl, and wherein m is an integer from 1 to 8; and n is    an integer from 0 to 8.

The present invention also relates to pharmaceutical formulationscontaining, a compound of formula I.

In another embodiment, the pharmaceutical formulation of the presentinvention may be adapted for use in treating obesity and relateddiseases.

The present invention also relates to methods for treating obesity in apatient in need thereof, wherein such treatment comprises administeringto said patient a therapeutically effective amount of a compound offormula I in association with a pharmaceutically acceptable carrier,diluent or excipient.

The present invention also relates to a method for antagonizing thebinding of MCH to MCH receptors for the treatment of diseases caused, orexercabated by melanin concentrating hormone.

The present invention provides the use of a compound of formula I as anappetite suppressant and/or as a weight loss agent.

The present invention is related to the use of a compound of formula Ifor the manufacture of a medicament for treating obesity and relateddiseases.

BRIEF DESCRIPTION OF THE DRAWINGS

-   -   FIG. 1: Effect of compound from Example 136 on MCH-stimulated        food intake in rats following ICV administration.

DETAILED DESCRIPTION

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below.

The term “main chain” as used herein describes the number of atoms inthe shortest distance between two ends of a variable or radical andincludes the distance in number of atoms when traversing a straightchain, branched chain or atoms in a mono or bicyclic ring from one endof the variable or radical to the other.

The term “C₁–C₈ alkyl” represents a straight, branched hydrocarbonmoiety having from one to eight carbon atoms, including but not limitedto methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, cyclobutyl, pentyl, hexyl, and the like.

The term “C₃–C₈ cycloalkyl” as used herein refers to a cyclichydrocarbon radical or group having from 3 to 8 carbon atoms and havingno double bonds. Examples of C₃–C₈ cycloalkyl groups include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl.

The term “C₃–C₈ cycloalkenyl” as used herein referes to a cyclichydrocarbon radical or group having from 3 to 8 carbon atoms and havingfrom 1 to 3 double bonds. Specific examples of C₃₋₈ cycloalkenyl includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, tetrahydrothiophene, tetrahydrofuran,

The term “halo” means halogens including iodo, chloro, bromo and fluoro.

The term “C₁–C₄ haloalkyl” refers to a C₁–C₄ alkyl group substitutedwith one, two or three halogen atoms as possible and appropriate.Examples of C₁–C₄ haloalkyl include but are not limited totrifluoromethyl, chloroethyl, and 2-chloropropyl. Similarly, a “C₁–C₈haloalkyl” group is a C₁–C₈ alkyl moiety substituted with up to six haloatoms, preferably one to three halo atoms.

A “C₁–C₈ alkoxy” group is a C₁–C₈ alkyl moiety connected through an oxylinkage. The term includes “optionally halogenated C₁₋₈ alkoxy” groupsincluding for example, C₁₋₈ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, pentyloxy, etc.), which may have 1 to 5, preferably 1 to 3,halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Concreteexamples of alkoxy groups include methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy.

The term “cyclic” as used herein refers to substituted or unsubstitutedaromatic and non-aromatic ring structures containing hydrocarbon groups,and substituted or unsubstituted aromatic and non-aromatic heterocyclicgroups. Cyclic groups may also be monocyclic, bicyclic or polycyclicunless otherwise specified. Examples of aromatic groups include, forexample, benzene, thiophene, furan, pyrrole, imidazole, pyrazole,thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine,pyrazine, pyrimidine, pyridazine, napthyl, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4,-thiadiazole, 1,3,4-thiadiazole, pyrrolidine,imidazoline, imidazolidine, pyrazoline, pyrazolidine,tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole,tetrahydroisoxazole, piperidine, tetrahydropyridine, dihydropyridine,piperazine, morpholine, thiomorpholine, tetrahydropyrimidine,tetrahydropyridazine, hexamethyleneimine, benzofuran, benzimidazole,benzoxazole, benzothiophene, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, isoquinoline, quinoline, indole, quinoxaline,phenanthridine, phenothiazine, phenoxathlin, phenoxazine, naphthylidene,quinazoline, carbazole, b-carboline, acridine, phenazine, phthalimide,and thioxanthene each of which may be optionally substituted.

The term alkylcycloalkyl” as used herein refers to an alkylgroup onwhich a cycloalkyl group is substituted. Exemplary of alkylcycloalkylgroups are methylcyclopropyl, methylcyclohexyl, methylcycloheptyl,ethylcyclopropyl, etc. The alkylcycloalkyl group may optionally besustituted independently with one to five groups selected from C₁–C₈alkyl, phenyl, aryl, halo, amino, alkysulfonyl, alkylsulfonamide,haloalkyl, carboxyalkyl, carboxamide, alkoxy, and perfluoroalkoxy.

The term “optionally substituted” as used herein and unless otherwisespecified, means an optional substitution of one to five, preferably oneto two groups independently selected from halo, hydroxy, oxo, cyano,nitro, phenyl, benzyl, triazolyl, tetrazolyl, 4,5-dihydrothiazolyl,halo, C₁–C₆ alkyl, C₁–C₄ haloalkyl, C₁–C₆ or a pharmaceuticallyacceptable salt, solvate, enantiomer, mixture of enatiomers or prodrugthereof wherein

-   Ar¹ is a cyclic group optionally substituted with one to five groups    selected from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy,    C₁–C₈ alkoxy, C₁–C₈ alkylaryl, phenyl, —O-aryl, heteroaryl,    cycloalkyl, C₁–C₈ alkylcycloalkyl, cyano, —(CH₂)_(n)NR⁶R⁶, C₁–C₈    haloalkyl, C₁–C₈ haloalkoxy, halo, (CH₂)_(n)COR⁶, (CH₂)_(n)NR⁵SO₂R⁶,    —(CH₂)_(n)C(O)NR⁶R⁶, heterocyclic, and C₁–C₈ alkylheterocyclic;    wherein the cycloalkyl, phenyl, aryl, and heterocyclic    susbstitutents are each optionally substituted with one to three    groups selected from hydroxy, C₁–C₈ alkoxyalkyl, C₁–C₈ haloalkoxy,    C₁–C₈ alkyl, halo, C₁–C₈ haloalkyl, nitro, cyano, amino,    carboxamido, phenyl, aryl, alkylheterocyclic, heterocyclic, and oxo;-   L¹ is a bond or a divalent linker having a main chain of 1 to 10    atoms; or represented by the formula X₂—(CR³R⁴)_(m)—X₃ where X₂ is    attached to Ar¹ and X₃ is attached to AR² wherein R³ and R⁴ are    independently selected from a bond, hydrogen, C₁–C₈ alkyl, C₂–C₈    alkylene, C₂–C₈ alkynyl, phenyl, aryl, C₁–C₈ alkylaryl; wherein the    alkyl, alkenyl, phenyl, and aryl groups are optionally substituted    with one to five substitutents independently selected from oxo,    nitro, cyano, C₁–C₈ alkyl, aryl, halo, hydroxy, C₁–C₈ alkoxy, C₁–C₈    halaoalkyl, (CH₂)_(n)C(O)R⁶, and (CH₂)_(n)CONR⁶R⁶;-   X₂ is independently oxygen, —CH, —CONH(CR³R⁴)_(m), —NHCO(CR³R⁴)_(m),    —(CR³R⁴)_(m), —CHR⁶, —NR⁵, S, SO, SO₂, —O(CR³R⁴)_(m), or    —S(CR³R⁴)_(m);-   X₃ is independently oxygen, —C, —CH, —CHR⁶, —(CR³R⁴)_(m), —NR⁵, S,    SO, or SO₂;-   AR² is a 5-member monocyclic heterocyclic aromatic group or    positional isomer thereof, having 1, 2, or 3 heteroatoms    independently selected from nitrogen, oxygen and sulfur;    and optionally substituted with one to three substitutents selected    from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy, C₁–C₈    alkoxy, C₁–C₈ alkylaryl, phenyl, aryl, C₃–C₈ cycloalkyl, C₁–C₈    alkylcycloalkyl, cyano, C₁–C₈ haloalkyl, halo, (CH₂)_(n)C(O)R⁶,    (CH₂)_(n)C(O)OR⁶, (CH₂)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR⁶R⁶, and C₁–C₈    alcylheterocyclic;-   AR³ is a 6-member monocyclic, aromatic, carbocyclic or heterocyclic    ring having 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen    and sulfur and which is optionally substituted with one to three    substituents independently selected from C₁–C₈ alkyl, C₂–C₈ alkenyl,    C₂–C₈ alkynyl, halo, —NHR⁵, C₁–C₈ haloalkyl, C₃–C₈ cycloalkyl,    hydroxy, alkoxy, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶,    (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR⁶R⁶, phenyl, C₁–C₈ alkylaryl, and    aryl;-   L² is a divalent linker having a chain length of between 1 and 10    atoms in the main chain or is represented by the formula:    X₄—(CR³R⁴)_(m)—X₅;    wherein X₄ is selected from the group consisting of C, —CH, CHR⁶,    —CO, O, —NR⁵, —NC(O)—, —NC(S), —C(O)NR⁵—, —NR^(6′)C(O)NR⁶,    —NR^(6′)C(S)NR⁶, —SO₂NR⁷, —NRSO₂R⁷, and —NR^(6′)C(NR⁵)NR⁶;-   X₅ is selected from the group consisting of —CH₂, —CH,    —O(CR³R⁴)_(m), NR³(CR³R⁴)_(m), SO, SO₂, S, and SCH₂; wherein the    group X₄—(CR³R⁴)_(m)—X₅ imparts stability to the compound of    formula (1) and may be a saturated or unsaturated chain or divalent    linker.-   Q is a basic group or a group represented by —NR¹R²; wherein-   R¹ and R² are independently hydrogen, C₁–C₈ alkyl, C₂–C₈ alkenyl,    C₃–C₈ cycloalkane, C₁–C₈ alkylaryl, —C(O)C₁–C₈ alkyl, —C(O)OC₁–C₈    alkyl, C₁–C₈ alkylcycloalkane, (CH₂)_(n)C(O)OR⁵, (CH₂)_(n)C(O)R⁵,    (CH₂)_(n)C(O)NR⁶R⁶, and (CH₂)_(n)NSO₂R⁵; wherein each of the alkyl,    alkenyl, aryl are each optionally substituted with one to five    groups independently selected from C₁–C₈ alkyl, C₂–C₈ alkenyl,    phenyl, and alkylaryl; and-   wherein R¹ and R² may combine together, and with the nitrogen atom    to which they are attached or with 0, 1, 2 or 3 atoms adjacent to    the nitrogen atom to form a nitrogen containing heterocycle which    may have 1, or 2 substituents independently selected from CL-CS    alkyl, C₂–C₈ alkenyl, C₃–C₈ cycloalkane, C₁–C₈ alkylaryl, —C(O)C₁–C₈    alkyl, —C(O)OC₁–C₈ alkyl, C₁–C₈ alkylcycloalkane, oxo, halo amino,    and (CH₂)_(n)C(O)NR⁶R⁶; provided that L²-Q is not CONH₂; wherein R¹    and R² may combine with the nitrogen atom to which they are attached    to form and imine; and provided that Q is not a subsituent on an    amide;-   R⁵ is hydrogen, CN, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₅–C₈ alkylaryl,    (CH₂)_(n)NSO₂C₁–C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,    —C(O)C₁–C₈ alkyl, or —C(O)OC₁–C₈ alkyl; and-   R⁶ and R⁶′ are independently hydrogen, C₁–C₉ alkyl, phenyl, aryl,    C₁–C₈alkylaryl, or C₃–C₈cycloalkyl; wherein m is an integer from 1    to 8; and n is an integer from 0 to 8. where R⁷ is independently at    each occurrence H, C₁–C₆ alkyl, phenyl or benzyl and R⁸ is    independently at each occurrence C₁–C₆ alkyl, phenyl or benzyl.

The term “heterocycle or heterocyclic” represents a stable, saturated,partially unsaturated, fully unsaturated or aromatic 4, 5, or 6 memberedring, said ring having from one to three heteroatoms that areindependently selected from the group consisting of sulfur, oxygen, andnitrogen. The heterocycle may be attached at any point which affords astable structure. Representative heterocycles include 1,3-dioxolane,4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole,imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole,oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine,pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole.

The heterocycle is further optionally substituted with one to three,preferably one or two groups independently selected from halo, hydroxy,oxo, cyano, nitro, phenyl, benzyl, triazolyl, tetrazolyl,4,5-dihydrothiazolyl, C₁–C₆ alkyl, C₁–C₄ haloalkyl, C₁–C₆ alkoxy, COR⁷,CONR⁷R⁷, CO₂R, NR⁷R⁷, NR⁷COR⁷, NR⁷SO₂R, OCOR⁸, OCO₂R⁷, OCONR⁷R⁷, SR⁷,SOR⁸, SO₂R and SO₂(NR⁷R⁷), where R⁷ is independently at each occurrenceH, C₁–C₆ alkyl, phenyl or benzyl and R is independently at eachoccurrence C₁–C₆ alkyl, phenyl or benzyl.

The term “alkylheterocyclic” as used herein refers to an alkyl groupfurther substitued with a heterocyclic group. Examples ofalkylheterocycles include but are not limited to 2-methylimidazoline,N-methyhnorpholinyl, N-methylpyrrolyl and 2-methylindolyl.

The term “basic group” refers to an organic radical which is a protonacceptor. The term “basic group” also refers to an organic groupcontaining one or more basic radicals. Illustrative basic radicals areamidino, guanidino, amino, piperidyl, pyridyl, etc, and excludes amides.

Suitable basic radicals contain one or more nitrogen atoms and includeamino, imino, amidino, N-alkylamidines, N,N′-dialkylamidines,N-arylamidines, aminomethyleneamino, iminomethylamino, guanidino,aminoguanidino, alkylamino, dialkylamino, trialkylatnino,alkylideneamino, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, amide,thioamide, benzamidino, pteridinyl, 4H-carbazolyl, carbazolyl,beta-carbolinyl, phenantrrridinyl, acridinyl, pyrimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, or anyof the preceding substituted with amino, imino, amidino,aminomethyleneamino, iminomethylamino, guanidino, alkylamino,dialkylamino, trialkylamino, tetrahydroisoquinoline, dihydroisoindole,alkylideneamino, groups, or a group represented by the formula NR¹R².

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction, that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats and the like) and livestockanimals. Livestock animals are animals raised for food production.Ruminants or “cud-chewing” animals such as cows, bulls, heifers, steers,sheep, buffalo, bison, goats and antelopes are examples of livestock.Other examples of livestock include pigs and avians (poultry) such aschickens, ducks, turkeys and geese. Yet other examples of livestockinclude fish, shellfish and crustaceans raised in an aquaculture. Alsoincluded are exotic animals used in food production such as alligators,water buffalo and ratites (e.g., emu, rheas or ostriches). The preferredpatient of treatment is a human. The terms “treating” and “treat”, asused herein, include their generally accepted meanings, i.e.,preventing, prohibiting, restraining, alleviating, ameliorating,slowing, stopping, or reversing the progression or severity of apathological condition, or sequela thereof.

The terms “preventing”, “prevention of”, “prophylaxis”, “prophylactic”and “prevent” are used herein interchangeably and refer to reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” means an amount of acompound of formula I that is sufficient for treating or preventing acondition, or detrimental effects thereof, herein described, or anamount of a compound of formula I that is sufficient for antagonizingthe MCHR¹ receptor to achieve the objectives of the invention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “formulation”, as in pharmaceutical formulation, is intended toencompass a product comprising the active ingredient(s) (compound(s) offormula I), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier, or a compound of theformula I and a pharmaceutically acceptable co-antagonist of MCHR1useful for the treatment and/or prevention of obesity or a relateddisease where antagonism of a MCH receptor may be beneficial.

The terms “diseases related to obesity” or “related diseases” as usedherein refers to such symptoms, diseases or conditions caused by,exacerbated by, induced by, or adjunct to the condition of being obese.Such diseases, conditions and/or symptoms include but are not limited toeating disorders (bulima, anorexia nervosa, etc.), diabetes, diabeticcomplications, diabetic retinopathy, sexual/reproductive disorders,depression, anxiety, epileptic seizure, hypertension, cerebralhemorrhage, conjestive heart failure, sleeping disorders,atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia,hypertriglycemia, hyperglycemia, and hyperlipoproteinenamia.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and other non-human animals (asdescribed above), each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier. Because certaincompounds of the invention contain an acidic moiety (e.g., carboxy), thecompound of formula I may exist as a pharmaceutical base addition salt.

Such salts include those derived from inorganic bases such as ammoniumand alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like.

Because certain compounds of the invention contain a basic moiety (e.g.,amino), the compound of formula I may also exist as a pharmaceuticalacid addition salt. Such salts include the salicylate, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, β-hydroxybutyrate, oxalate, glycolate,maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and likesalts. Preferred acid addition salts include the hydrochloride andoxalate salts. Acid addition salts are typically formed by reacting anequivalent amount of acid (based on moles of available basic i.e freepairs of electrons on nitrogen atoms, or a slight excess thereof) withthe free base compound of the invention. The addition salt product isoften isolated as the crystallization product. The crystallization maybe spontaneous or may be facilitated by cooling and/or seeding. Othermethods of isolating the acid addition salts are known to one of skillin the art.

PREFERRED COMPOUNDS OF THE INVENTION

Certain compounds of the invention are particularly interesting andpreferred. The following listing sets out several groups of preferredcompounds. It will be understood that each of the listings may becombined with other listings to create additional groups of preferredcompounds.

Preferred Ar¹

Preferred Ar¹ groups are cyclic groups selected from cycloallyl andcycloalkene groups such as the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl. Also preferred are groups selected fromtetrahydrothiophene, tetrahydrofuran, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, tetrahydrothiazole,tetrahydroisothiazole, tetrahydrooxazole, phenyl, tetrahydroisoxazole,piperidine, tetrahydropyridine, benzothiophene, benzofuran, naphthyl,dihydropyridine, piperazine, morpholine, thiomorpholine,tetrahydropyrimidine, tetrahydropyridazine, hexamethyleneimine, eachoptionally substituted with C₁–C₆ alkyl, C₁–C₆ cycloalkyl, C₁–C₆haloalkyl, hydroxy, alkoxyalkyl, cyano, halo, aryl, carboxamide, andC₁–C₆ carboxyalkyl. More preferred Ar¹ groups include cycloalkyl,cycloalkenyl, substituted or unsubstituted phenyl, benzothiophene,benzofuran and naphthyl.

Preferred L¹ Groups

Preferred as L¹ are groups having between 3 to 8 carbon atoms in themain chain. Also preferred are L¹ groups selected from the groupconsisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —SCH₂—, —OCH₂—, CH₂SCH₂—,—CH₂OCH₂—, —CH₂CH₂SCH₂—, —OCH₂CH₂OCH₂—, —O(CH₂)₃SCH₂—,—OCH(Et)CH₂CH₂SCH₂, —OCH(iPr)CH₂CH₂SCH₂, —OCH(CH₃)CH₂CH₂SCH₂,—O(CH₂)₃SCH(CH₃)—, —O(CH₂)₂SCH(CF₃)—, —OCH₂CH(NO₂)SCH₂—,—OCH(CN)CH₂SCH₂, —OCH₂CH(NH₂)SCH₂—, —CH₂O(CH₂)₃CH₂O—, and—CH₂O(CH₂)₂CH₃O—

Preferred X₂ Group

Also preferred is an L¹ group having the formula X₂—(CR³R⁴)_(m)—X₃wherein a preferred X₂ group is selected from O, S, and —NR⁶, andwherein R⁶ is selected from the group consisting of hydrogen, C₁–C₆alkyl, C₂–C₆ alkenyl, C₃–C₈ cycloalkyl, phenyl, benzyl, C₁–C₈alkylamine, and aryl.

Preferred X₃ Groups

Also preferred is an L¹ group wherein, when L¹ is X₂—(CR³R⁴)_(m)—X₃;wherein X₃ is a group selected from —OCH₂, —SCH₂, —NR⁶C(O)CH₂, —NHCH₂,wherein R⁶ is selected from the group consisting of hydrogen, C₁–C₆alkyl, C₂–C₆ alkenyl, C₃–C₈ cycloalkyl, phenyl, benzyl, and aryl. Morepreferred is an X₃ group selected from —OCH₂, and —SCH₂.

Also preferred is a compound of formula I wherein L¹ isX₂—(CR³R⁴)_(m)—X₃, and wherein the chain between X₂ and X₃ i.e.,—(CR³R⁴)_(m)— is an alkyl chain of 3 to 8 carbon atoms, or an alkenylchain of 3 to 8 carbon atoms and optionally contains an alkyl, phenyl,amino, or cycloalkyl group as a side chain.

Preferred AR² Groups

A preferred Ar² group is a 5-member monocyclic aromatic heterocyclicgroup having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, andnitrogen. More preferred is a heterocyclic group selected from furan,thiophene, pyrrole, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, 2-pyraziline, pyrazolidine, isoxazole,isothiazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole and1,3,4-oxadiazole. Most preferred AR² are the oxadiazolyl or oxazolylgroups, and positional isomers thereof.

Preferred Ar³ Groups

Preferred Ar³ group is a 6-member carbocyclic or heterocyclic grouphaving 0, 1, 2, or 3 heteroatoms independently selected from oxygen,sulfur, and nitrogen and optionally substituted with one to two groups.More preferred is a cyclic group selected from phenyl, pyran,piperidine, pyridine, pyridazine, and piperazine. Most preferred AR³ isphenyl.

Preferred L² Groups

Preferred L² groups include a divalent group having between 3 and 8atoms in the main cahin. Also preferred are L² groups selected from thegroup consisting of —OCH₂CH₂—, —O(CH₂)₃—, —CH₂, —CH₂CH₂, —CH₂CH₂CH₂,—CH═CH, —CH₂CH₂CH═CH— and X₄—(CR³R⁴)_(m)—X₅.

Preferred X₄ Groups

Preferred X₄ groups include divalent groups, radicals, or fragments ofthe formula —C(O)NR⁶ wherein R⁶ is selected from the group consisting ofhydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₃–C₈ cycloalkyl, phenyl, benzyl,C₁–C₈ alkylamine, and aryl.

Also preferred is an X₄ group selected from O, S, —NR⁶C(O)NR⁶, —C(S)NR⁶,NR⁶C(S)NR⁶, NR⁶C@4R⁶)NR⁶, —NR⁶SO₂—, wherein R⁶ is independently selectedfrom the group consisting of hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₃–C₈cycloalkyl, phenyl, benzyl, C₁–C₈ alkylamine, and aryl.

Preferred X₅ Groups

Preferred is an X₅ group selected from —OCH₂, —SCH₂, O, —NR⁶C(O),—NR⁶C(S), —C(O)NR⁶, —C(S)NR⁶, NR⁶C(S)NR⁶, NC(NR⁶)N, NR⁶C(O)NR⁶, —NR⁶SO₂wherein R⁶ is independently selected from the group consisting ofhydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₃–C₈ cycloalkyl, phenyl, benzyl,C₁–C₈ alkylamine, and aryl. More preferred is an X₅ group selected fromOCH₂, SCH₂ and O.

Also preferred is a compound of formula I wherein the chain between X₄and X₅ is preferably an alkyl chain of 2 to 8 carbon atoms, or analkenyl chain of 2 to 8 carbon atoms and optionally containing an alkyl,phenyl, or cycloalkyl group as a side chain.

Preferred Q Groups:

The substituent Q of formula I is a basic group. A basic group is anorganic group containing one or more basic radicals. Preferred Q groupsare those represented by the formula —NR¹R²

Preferred R¹ and R² Groups

Preferred R¹ and R¹ groups are independently selected from the groupconsisting of hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₃–C₈ cycloalkyl,C₃–C₈₁₀ alkylcycloalkyl, phenyl, benzyl, COR⁹, SO₂R⁹, and(CH₂)_(n)SO₂R⁶.

Also preferred are R¹ and R² groups which combine with each other, thenitrogen atom to which they are attached to form a heterocycle selectedfrom morpholino, thiomorpholino, pyrrole, 2H-pyrrole, 2-pyrroline,pyrrolidine, oxazole, thiazole, imidazoline, imidazolidine, pyrazole,pyrazoline, piperazinyl, piperadinyl, pyrazinyl, pyrimidine eachoptionally substituted with a C₁–C₈ alkyl group.

Also preferred is a compound of the invention having R¹ and R² groupswherein the R¹ and R² groups combine with the nitrogen atom to whichthey are attached and with a carbon atom one or two atoms removed fromthe nitrogen atom to form a cycle such as for example, azepine,diazepine, pyridine, piperidine, indolyl, N-methylpyrrolidinyl,pyrrolidinyl, morpholino, piperidinyl, and the like.

Also preferred are compounds of formula I wherein R¹ and R² combinetogether with the nitrogen atom to which they are attached to form animine or substituted imine.

Most preferred are R₁ and R₂ which singly or in combination with eachother and/or the nitrogen atom to which they are attached form thegroups independently selected from methyl, ethyl, propyl, isopropyl,isobutyl, cyclopentyl, cyclohexyl, N-morpholino, azepane, diazepine,pyridine, pyrrolidine, piperidine, N-methylpiperidine, andN-methylpiperazine.

Preferred R³ and R⁴ Groups:

Preferred R³ and R⁴ are independently selected from hydrogen, C₁–C₈alkyl, C₂–C₈ alkylene, C₂–C₈ alkynyl, phenyl, aryl, C₁–C₈ alkylaryl,(CH₂)_(n)NR⁵SO₂R, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR⁶R⁶ and(CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl, phenyl, and aryl groupsare optionally substituted with one to three substitutents independentlyselected from oxo, nitro, cyano, C₁–C₈ alkyl, aryl, halo, hydroxy, C₁–C₈alkoxy, C₁–C₈ halaoalkyl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR⁶R⁶ and(CH₂)_(n)C(O)OR⁶.

Most preferred R³ and R⁴ substituents are independently selected fromhydrogen, C₁–C₈ alkyl, C₂–C₈ alkylene, C₂–C₈ alkynyl, phenyl, andbenzyl; and wherein n is 0, or 1, and wherein R⁵ is hydrogen, C₁–C₈alkyl, phenyl or benzyl; and wherein R⁶ is hydrogen, C₁–C₈ alkyl, phenylor benzyl.

Preferred R⁵ Groups

A preferred R⁵ group is a group independently selected from hydrogen,C₁–C₈ alkyl, C₁–C₈ alkoxy, C₂–C₈ alkenyl, C₅–C₈ alkylaryl,(CH₂)_(n)NSO₂C₁–C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,—C(O)C₁–C₈ alkyl, —C(O)OC₁–C₈ alkyl; and

Preferred R⁶ Groups

A preferred R⁶ or R⁶′ is independently selected from hydrogen, C₁–C₈alkyl, phenyl, aryl, alkylaryl, and C₃–C₈ cycloalkyl.

An example of a preferred compound of the present invention is acompound selected from the group consisting of:1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-dimethylamino-ethyl)-urea,

-   1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea,-   1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea,-   1-(3-{4-[5-(Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperidine,-   Cyclohexyl-ethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine,-   4-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-morpholine,-   1-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azepane,-   Diethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine,-   1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-piperidine,-   (3-{2–Chloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine,-   1-Methyl-4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-piperazine,-   (3-{2-Fluoro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine,-   Ethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine,-   Cyclopentyl-methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine,-   1-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azocane,-   Diethyl-(2-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-ethyl)-amine,-   Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine,-   Dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenoxy}-propyl)-amine,-   2-{4-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propenyl)-phenyl]-[1,3,4]oxadiazole,-   Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-furan-2-yl]-phenoxy}-propyl)-amine,-   4-Dimethylamino-N-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-butyramide,-   1-(2-Dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   1-(3-Dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   Dimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine,-   1-(2-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-piperidine,-   Dimethyl-(5-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-pent-4-enyl)-amine,-   2-(2-Dimethylamino-ethoxy)-N-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-acetamide,-   Dimethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[11,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine,-   1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperidine,-   Diethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,-   1-(4-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-piperidine,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(4-pyrrolidin-1-yl-butoxy)-phenyl]-[1,3,4]oxadiazole,-   1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-azepane,-   1-(2-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-azepane,-   Methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,-   Diethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine,-   1-(2-Dimethylamino-ethyl)-1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-[1,3,4]oxadiazole,-   1-(5-Dimethylamino-pentyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   1-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea,-   1-(4-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-azepane,-   Diethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine,-   1-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea,-   1-(2-Dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   (3-{4-[S-(Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(5-pyrrolidin-1-yl-pent-1-enyl)-phenyl]-[1,3,4]oxadiazole,-   1-(5-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-pent-4-enyl)-piperidine,-   1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperidin-4-one,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole,-   Dimethyl-(2-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-ethyl)-amine,-   1-(2-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-ethyl)-piperidine,-   1-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-piperidine,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-oxazole,-   Dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-amine,-   Dimethyl-(6-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-hex-5-enyl)-amine,-   Dimethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-but-3-enyl)-amine,-   Dimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenoxy}-propyl)-amine,-   (3-{4-[5-(Benzo[b]thiophen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine,-   Dimethyl-(3-{4-[5-(naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,-   Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,3,4]oxadiazole,-   2-[4-(3-Azetidin-1-yl-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole,-   1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea,-   1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea,-   1-(2-Dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-urea,-   1-(2-Dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-urea,-   1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-urea,-   1-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-urea,-   N,N-dimethyl-N-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-ethane-1,2-diamine,-   N,N-Dimethyl-N′-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-propane-1,3-diamine,-   1-Methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-piperidine,-   2-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propenyl)-phenyl]-oxazole,-   1-(2-Diethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea,-   5-(2-Phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]oxadiazole,-   Dimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-ethyl)-amine,    and pharmaceutically acceptable salts, solvates, enantiomers,    diasteromers and mixture of enantiomers thereof.

A most preferred compound of the present invention is selected from thegroup consisting of:

or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, ormixture of enantiomers thereof.

Preparing Compounds of the Invention

Compounds of formula I may be prepared as described in the followingSchemes and Examples. Precursors to the compounds of the invention areprepared by methods known to one of skill in the art. The compoundsemployed as initial starting materials in the synthesis of the compoundsof the invention are well known and, to the extent not commerciallyavailable, are readily synthesized by standard procedures commonlyemployed by those of ordinary skill in the art. More particularly, thecompounds of the invention are produced in accordance with the GeneralMethods 1 through 5 that are described in detail below, or analogousmethods thereto. These reactions are often carried out in accordancewith per se known methods, or analogous methods thereto. Examples ofsuch known methods include the methods described in general referencetexts such as Organic Functional Group Preparations, 2^(nd) Edition,1989; Comprehensive Organic Transformations, VCH Publishers Inc, 1989;Compendium of Organic Synthetic Methods, Volumes 1–10, 1974–2002, WileyInterscience; March's Advanced Organic Chemistry, Reactions Mechanisms,and Structure, 5^(th) Edition, Michael B. Smith and Jerry March, WileyInterscience, 2001, Advanced Organic Chemistry, 4^(th) Edition, Part B,Reactions and Synthesis, Francis A. Carey and Richard J. Sundberg,Kluwer Academic/Plenum Publishers, 2000, etc., and references citedtherein.

General Method 1: Coupling of the Basic Group

The compounds of Formula 3 can be prepared by the General Method 1,described in General Scheme 1, via coupling of a compound of Formula 2containing a basic group with a group of Formula 1, where during thecourse of the coupling reaction the coupling groups are retained or lostto form the linker L² between the basic group and the phenyl ring. Ar¹,L¹, Ar², L², and basic group are defined as above. In the schemes thatfollow AR³ of formula I has been depicted as a phenyl group forconvenience only and is not intended to be limiting. Also, L_(a) isdefined as a group that when the coupling process occurs results in theformation of the linker L² defined above. Furthermore, in the schemesthat follow, the group L¹ is depicted by the combination of group orgroups interspacing or linking the groups AR¹ and AR². Similarly, thegroup L² is depicted by the combination of group or groups interspacingor linking the groups AR³ and the basic group. The basic group of thecompounds of the follewoing schemes in general mean the group —N(R¹R²)unless otherwise indicated. Examples of the General Method 1 are aDisplacement Process (Scheme 1a) and a Reductive Amination Process(Scheme 1b).

As outlined in Scheme 1a below, the coupling process of General Method 1may consist of a displacement process whereby nucleophilic displacementof a leaving group, such as, but not limited to, halogen, triflate,tosylate, brosylate, mesylate, nosylate, nonaflate, tresylate, and thelike, of Formula 4, by a nucleophilic basic group of Formula 5 affordsthe compounds of the invention. A leaving group is defined in one ormore of the general reference texts described previously.

One to five equivalents of the nucleophilic basic group of Formula 5 andone to five equivalents of the reactive derivative of Formula 4 may bereacted in the presence, or absence, of an inert solvent. If necessary,the reaction may be carried out in the presence of a catalytic quantityto about five equivalents of a non-interfering base. A non-interferingbase is a base suitable for the intended reaction by virtue of the basenot deleteriously affecting the reaction. One to two equivalents of baseis normally preferable. The reaction is normally carried out between 0°C. and 120° C. Reaction time is normally 4 to 24 hours.

Nucleophilic basic groups would include, but would not be limited toammonia, primary and secondary amines, guanidines, and the like.Specific nucleophilic basic groups include ammonia, methylamine,dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine,morpholine, azetidine, thiomorpholine, piperazine, imidazole, and thelike. Among the above nucleophilic basic groups dimethylamine,pyrrolidine, and piperidine are preferable.

If necessary, the reaction can be carried out with nucleophilic basicgroup synthon, i.e., a group that could readily be converted to a basicgroup by methods known to one skilled in the art. Nucleophilic basicgroup synthons would include, but would not be limited to, azide,phthalimide, protected amines, hexamethylenetetramine, cyanamide,cyanide anion, and the like. Following the displacement reaction, thesegroups would then be unmasked under standard conditions to afford thebasic group. For example, displacement with potassium phthalimidefollowed by removal of the phthalimide group to afford the primary amineas in the Gabriel synthesis (see, March's Advanced Organic Chemistry,Reactions Mechanisms, and Structure, 5^(th) Edition, Michael B. Smithand Jerry March, Wiley Interscience, 2001, Chapter 10, and referencescited therein). Application of the synthon equivalent to the basic groupapplies to the processes described in all of the General Methods 1through 5.

Examples of “inert solvent” includes amide solvents (preferably DMF orDMAC), sulfoxide solvents (preferably DMSO), sulfone solvents(preferably sulfolane or dimethylsulfone), nitrile solvents (preferablyacetonitrile), halogenated hydrocarbon solvents (preferablydichloromethane), aromatic solvents (preferably toluene or benzene),ether solvents (preferably diethylether or THF), ketone solvents(preferably acetone), ester solvents preferably ethyl acetate), alcoholsolvent (preferably MeOH or EtOH), etc. Two or more of the solvents canbe mixed in an appropriate ratio for use. Among the above solvents, DMFand DMSO are preferable.

Examples of “base” include, for instance, hydrides of alkali metals andalkaline earth metals (e.g., lithium hydride, sodium hydride, potassiumhydride, and the like), amides of alkali metals and alkaline earthmetals (e.g., sodium amide, lithium diisopropyl amide, lithiumhexamethyldisilazide, and the like), alkoxides (e.g. sodium methoxide,sodium ethoxide, potassium t-butoxide, and the like), inorganic bases,such as hydroxides of alkali metals or alkaline earth metals (e.g.,sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like),carbonates and hydrogen carbonates of alkali metals or alkaline earthmetals (e.g., potassium carbonate, sodium bicarbonate, sodium carbonate,cesium carbonate, and the like), amine bases (such as,N-methylmorpholine, DBU, DBN, pyridine, 2,6-lutidine, triethylamine,diisopropylethylamine, and the like). Among the above bases, sodiumhydride, potassium carbonate, and cesium carbonate are preferable.

As outlined in Scheme 1b below, the coupling process can consist of aReductive Amination Process. A compound of Formula 6 is condensed withammonia, or a primary, or secondary amine under dehydration/reductionconditions. Scheme 1b is a process analogous to that described in forexample, Chem Pharm Bull 1999, 47 (8), 1154–1156; Synlett 1999, (11),1781–1783; and J Med Chem 1999, 42 (26), 5402–5414 and references citedtherein.

The carbonyl compound of Formula 6 is reacted with an amine of Formula 7in an inert solvent under conditions that form the iminium species ofFormula 8. The iminium species is reduced in-situ to form the compoundsof Formula 3. The reaction is normally done in the presence of adehydrating agent and a reducing agent. Amines of Formula 7 include, butare not be limited to ammonia, primary and secondary amines, and thelike. Specific amine groups include ammonia, methylamine, dimethylamine,diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine,azetidine, thiomorpholine, piperazine, imidazole, and the like. One tofive equivalents of the amine group of Formula 7 and one to fiveequivalents of the reactive derivative of Formula 6 are reacted in thepresence, or absence, of an inert solvent. The use of an excess ofdehydrating agent is normally preferable. The reaction is carried out inthe presence of one to hundred equivalents of a reducing agent. One tothree equivalents of reducing agent is preferable. The reaction isnormally carried out between 0° C. and 120° C. Reaction time is normally4 to 24 hours. For the above amination reaction, MeOH and EtOH arepreferable as inert solvents.

Examples of “dehydrating agents” may be anhydrous molecular sievesbeads, anhydrous molecular sieve pellets, powdered anhydrous molecularsieves, anhydrous molecular sieves on supports (such as zeolite),anhydrous magnesium sulfate, anhydrous sodium sulfate, and the like.Among the above dehydrating agents, anhydrous molecular sieves pelletsand powdered anhydrous molecular sieves are preferable.

Examples of “reducing agents” include hydrogen gas or hydrogen gasprecursor and a hydrogenation catalyst. Other “reducing agents” includesodium cyanoborohydride, sodium triacetoxyborohydride, sodiumborohydride, sodium borohydride/Ti (Oi-Pr)4, borohydride-exchange resin,and the like. Examples of “hydrogen gas precursors” include formic acid,1,4-cyclohexadiene, and the like. Examples of “hydrogenation catalyst”include palladium on carbon, platinum on carbon, rhodium, ruthenium,nickel and the like. The metal can be used as a finely dispersed solidor absorbed on a support, such as carbon or alumina. Among the abovereducing agents, sodium cyanoborohydride and sodiumtriacetoxyborohydride are preferred.

General Method 2: Coupling of the Linker Group

The compounds of Formula 3 can be prepared by the General Method 2,described in General Scheme 2, via reaction of the coupling group ofFormula 9 with a coupling group of Formula 10.

Examples of the General Method 2 are an Ether/Thioether AlkylationProcess (Scheme 2a), an Acylation/Sulfonylation Process (Scheme 2b),Urea/Thiourea/Guanidine Coupling Process (Scheme 2c1, 2c2, 2c3), anOrganometallic Process (Scheme 2d), and a Wittig-type Coupling (Scheme2e). As outlined in Scheme 2a below, the coupling process of GeneralMethod 2 can consist of a Ether/Thioether Alkylation Process.Nucleophilic displacement by an alcohol or thiol-containing compound ofFormula 11 (or Formula 11′) with a compound of Formula 12 (or Formula12′) containing a leaving group affords the ether and thioethercompounds of Formula 13. Scheme 2a is a process analogous to thatdescribed in The Chemistry of the Ether Linkage; Patai, Wiley, 1967,446, 460; and in March's Advanced Organic Chemistry, ReactionsMechanisms, and Structure, 5^(th) Edition, Michael B. Smith and JerryMarch, Wiley Interscience, 2001, Chapter 10.

One to five equivalents of the alcohol or thiol of Formula 11 (orFormula 11′) and one to five equivalents of the reactive derivative ofFormula 12 (or Formula 12′) are reacted in the presence, or absence, ofan inert solvent. If necessary, the reaction can be carried out in thepresence of a catalytic quantity to ten equivalents of a non-interferingbase. One to three equivalents of base is normally preferable. Thereaction is typically carried out between 0° C. and 120° C. Reactiontime is typically 4 to 24 hours, but may be longer depending on theparticular substrate. Preferred bases for the above reaction includesodium hydride, potassium carbonate and cesium carbonate. If necessary,the reaction may be carried out with basic group synthon incorporated asthe basic group in Formula 12, i.e., a group that could readily beconverted to a basic group by methods known to one skilled in the art.Basic group synthons would include, but not be limited to, halogen,protected amine, nitrile, aldehyde, and the like. Following theether/thioether alkylation reaction, these groups would then be unmaskedor converted under standard conditions to afford the basic group. Forexample, alkylation with 1-iodo-4-chloro-butane would give a4-chlorobutane derivative of compound 11. The chloride could then beconverted by the Displacement Process, described above in Scheme 1a,into the basic group of a compound of Formula 13. Among the inertsolvents, DMF and DMSO are preferable.

As outlined in Scheme 2b below, the coupling process of General Method 2can consist of a Acylation/Sulfonylation Process. Acylation orsulfonylation of an alcohol or amine compound of Formula 14 with acarboxylic acid or sulfonic acid compound of Formula 15, affords theester, amide, sulfonic ester, or sulfonamide compounds of Formula 16.Alternatively, acylation or sulfonylation of an alcohol or aminecompound of Formula 18 with a carboxylic acid or sulfonic acid compoundof Formula 17 affords the ester, amide, sulfonic ester, or sulfonamidecompounds of Formula 19. If necessary, the reaction can be carried outwith a basic group synthon incorporated as the basic group in Formula 15or Formula 18, i.e., a group that could readily be converted to a basicgroup by methods known to one skilled in the art. Basic group synthonswould include, but not be limited to, halogen, protected amine, nitrile,aldehyde, and the like. Following the Acylation/Sulfonylation reaction,these groups would then be unmasked or converted under standardconditions to afford the basic group.

The carboxylic acid (or sulfonic acid) residue of compound 15 (orcompound 17) is activated for coupling as a “reactive acylating agent.”“Reactive acylating agents” are described in detail in Advanced OrganicChemistry, 4^(th) Edition, Part B, Reactions and Synthesis, Francis A.Carey and Richard J. Sundberg, Kluwer Academic/Plenum Publishers, 2000,Chapter 3, and references cited therein. The “reactive acylating agent”can be formed and isolated, then reacted with the compound of Formula 14(or 18), or formed in situ and reacted with the compound of Formula 14(or 18), to form the compound of Formula 16 (or 19).

One to five equivalents of the “reactive acylating agent” of compound 15(or compound 17) and one to five equivalents of compound of Formula 14(or 18) are reacted in an inert solvent. If necessary the reaction maybe carried out in the presence of one to five equivalents of1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and (or) acatalytic quantity to five equivalents of a base. The reaction isnormally carried out between 0° C. and 120° C. Reaction time is normally4 to 48 hours.

Examples of “reactive acylating agent” of compound 15 (or compound 17)include acid halides (e.g., acid chloride, acid bromide, and the like),mixed acid anhydrides (e.g., acid anhydrides with C₁–C₆ alkyl-carboxylicacid, C₆–C₁₀ aryl-carboxylic acid, and the like), activated esters(e.g., esters with phenol which may have substituents,1-hydroxybenzotriazole, N-hydroxysuccinimide,1-hydroxy-7-azabenzotriazole, and the like), thioesters (such as,2-pyridinethiol, 2-imidazolethiol, and the like), N-acylimidazoles(e.g., imidazole, and the like), etc.

A “reactive acylation agent” may also be formed reacting the carboxylicacid (or sulfonic acid) residue of compound 15 (or compound 17) with adehydration/condensation agent. Examples of a “dehydration/condensationagent” include dicyclohexylcarbodimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodimide (EDCI),(2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the like.Preferred solvents for the above reaction include acetonitrile, THF, anddichloromethane. Preferred bases for the above reaction includetriethylamine, pyridine, and dimethylaminopyridine are preferable.

As outlined in Scheme 2c1, Scheme 2c2, and Scheme 2c3 below, thecoupling process of General Method 2 can consist of aUrea/Thiourea/Guanidine/Carbamate-Type Coupling Process. The processesdescribed are analogous to that described in U.S. Pat. Nos. 5,849,769and 5,593,993, and references cited therein.

One to five equivalents of the isocyanate, isothiocyanate, carbodiimideof Formula 20 and one to five equivalents of compound of Formula 21 arereacted in an inert solvent. The reaction is typically carried outbetween 0° C. and 150° C. Preferred reaction time is between 4 to 48hours. Preferred solvents for the above reaction include acetonitrile,DMF, DMSO, THF, and dichloromethane.

If necessary, the reaction can be carried out with a basic group synthonincorporated as the basic group wherein a synthon is as describedealier. Following the Urea/Thiourea/Guanidine/Carbamate-Type CouplingProcess, these groups would then be unmasked or converted under standardconditions to afford the basic group.

Approximately one equivalent of the compound of Formula 23 and oneequivalent of compound of Formula 24 and one equivalent of the compoundof Formula 25 are reacted in an inert solvent. The reaction is typicallycarried out between 0° C. and 150° C. Reaction time is normally 4 to 48hours. The sequence of addition depends upon the reactivity of theindividual reagents. The intermediate addition product may be isolatedand subsequently be condensed with the second reagent. The reaction mayor may not require the addition of a catalyst. Prefered solvents for theabove reaction include acetonitrile, DMF, DMSO, TBT, toluene,isopropanol, and dichloromethane. Acids and bases as describedpreviously may be used to catalyze the above reaction.

One to five equivalents of the isocyanate, isothiocyanate, carbodiimideof Formula 28 and one to five equivalents of compound of Formula 27 arereacted in an inert solvent. The reaction is normally carried outbetween 0° C. and 150° C. Reaction time is normally 4 to 48 hours.

As outlined in Schemes 2d below, the coupling process of General Method2 may consist of a Organometallic Coupling Process.

The compound of Formula 30 (or Formula 34) is coupled with anorganometallic compound of Formula 31 (or Formula 33) (containing abasic group, or basic group precursor) in an Organometallic CouplingProcess to afford the compounds of the invention of Formula 32.

“Organometallic Coupling Processes” include “palladium-catalyzed crosscoupling reactions,” such as, Heck-type coupling reactions, Suzuki-typecoupling reactions and Stille-type coupling reactions. Otherorganometallic coupling reactions include, organocuprate couplingreactions, Grignard coupling reactions, and the like. A generaldescription of Organometallic Coupling is given in detail in AdvancedOrganic Chemistry, 4^(th) Edition, Part B, Reactions and Synthesis,Francis A. Carey and Richard J. Sundberg, Kluwer Academic/PlenumPublishers, 2000, Chapters 7 and 8, and references cited therein.

In Scheme 2d. the compound of Formula 30 (or Formula 34) is coupled withthe organometallic reagent of Formula 31 (or Formula 33) in thepresence, or absence, of a transition metal catalyst, and/or a phosphineor arsine, and/or a base in an inert solvent. Other additives, such as,copper salts, silver salts, and the like may be added. Approximately oneequivalent of the compound of Formula 30 (or Formula 34) is reacted withone to five equivalents of the compound of Formula 31 (or Formula 33)with the appropriate additives in an inert solvent. The reaction isnormally carried out between −78° C. and 200° C. for between 4 to 72hours.

Examples of “organometallic reagents” include, organomagnesium,organozinc, mixed organocuprate, organostannane, or organoboroncompounds, and the like. Examples of “transition metal catalysts”include, palladium and nickel catalysts, such as, Pd(OAc)₂, Pd (PPh₃)₄,PdCl₂, Pd(PPh₃)Cl₂, Pd(OCOCF₃)₂, (CH₃C₄H₅P)₂PdCl₂, [(CH₃CH₂)₃P]₂PdCl₂,[(C₆H₁₁)₃P₁₂PdCl₂, [(C₆H₅)₃P]₂PdBr₂, Ni(PPh₃)₄,(C₆H₄CH═CHCOCH═CHC₆H₅)₃Pd, and the like. Among the above transitionmetal catalysts, Pd(OAc)₂, Ni(PPh₃)₄, and Pd(PPh₃)₄ are preferable.

Examples of “phosphines or arsines” include, a trialkyl ortriarylphosphine or arsine, such as triisopropylphosphine,triethylphosphine, tricyclopentylphosphine, triphenylphosphine,triphenylarsine, 2-furylphosphine, tri-o-tolylphosphine,tricyclohexylphosphine, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,2-(Di-t-butylphosphino)biphenyl, and the like. Among the above“phosphines and arsines,” tri-o-tolylphosphine, triphenylarsine, andtricyclohexylphosphine are preferable.

Examples of “other additives” include, copper salts, zinc salts, lithiumsalts, ammonium salts and the like. Among the above “other additives,”CuI, LiCl, and n-Bu₄N⁺Cr are preferable. If necessary, the reaction canbe carried out with a basic group synthon incorporated as the basicgroup as described previously. As outlined in Schemes 2e below, thecoupling process of General Method 2 can consist of a Wittig-typeCoupling Process. The compound of Formula 33 (or Formula 37) is coupledwith the phosphorus ylene (or ylide) reagent of Formula 34 (or Formula36) to afford the compounds of Formula 35 of the invention. A generaldescription of Wittig-type Coupling Reactions is given in detail ingeneral reference texts such as Advanced Organic Chemistry, 4^(th)Edition, Part B, Reactions and Synthesis, Francis A. Carey and RichardJ. Sundberg, Kluwer Academic/Plenum Publishers, 2000, Chapter 2, andreferences cited therein.

The compound of Formula 33 (or Formula 37) is coupled with thephosphorus ylene (or ylide) reagent of Formula 34 (or Formula 36) in thepresence, or absence, a base in an inert solvent to form the compoundsof the invention of Formula 35. Other additives, such as, lithium salts,sodium salts, potassium salts, and the like may be added. Approximatelyone to five equivalents of the compound of Formula 33 (or Formula 37) isreacted with one to five equivalents of the compound of Formula 34 (orFormula 36) with the appropriate additives an inert solvent. Thereaction is normally carried out between −78° C. and 120° C. for between2 to 72 hours. The Wittig reaction product may be reduced to form othercompounds of the invention using reducing agents known to one of skillin the art and/or described previously. Preferred bases for the aboveorganometallic reactions include, sodium hydride, DBU, potassiumt-butoxide, and lithium hexamethyldisilazide.

General Method 3: Coupling of the Five-membered Ring Heterocycle andPhenyl Groups

The compounds of Formula 3 can be prepared by the General Method 3,described in General Scheme 3, via coupling of the compounds of Formula38 with a compound of Formula 39. An example of the General Method 3 isa Aryl Coupling Process (Scheme 3a). The aryl-coupling reaction iscarried out in accordance with per se known methods, or analogousmethods thereto, such as those described in the general reference textsdiscussed previously.

The compound of Formula 44 (or Formula 45) is coupled with anorganometallic compound of Formula 43 (or Formula 46) in an ArylCoupling Process to afford the compounds of the invention of Formula 3.

The compound of Formula 44 (or Formula 45) is coupled with theorganometallic reagent of Formula 43 (Formula 46) in the presence, orabsence, of a transition metal catalyst, and (or) a phosphine or arsine,and (or) a base in an inert solvent. Other additives, such as, coppersalts, silver salts, and the like may be added. Approximately oneequivalent of the compound of Formula 44 (or Formula 45) is reacted withone to five equivalents of the compound of Formula 43 (Formula 46) withthe appropriate additives an inert solvent. The reaction is normallycarried out between −78° C. and 200° C. for between 4 to 72 hours.Examples of “organometallic reagents”, “transition metal catalysts”“phosphines or arsines” “other additives” and “base” have been describedpreviously.

General Method 4: Heterocycle Formation

The compounds of Formula 3 can be prepared by the General Method 4,described in General Scheme 4, via reaction of the compound of Formula47 containing a coupling group with a compound of Formula 48 containinga coupling group, where during the course of the coupling reaction thecoupling groups form the 5-membered ring heterocycle between the linkerL¹ and the phenyl ring. Ar¹, L¹, Ar², L², and basic group are defined asabove. Examples of heterocyclic ring forming reactions are given in

Comprehensive Heterocyclic Chemistry, Volumes 1–8, A. P. Katritzky andC. W. Rees Eds, Pergamon Press, 1984; Heterocyclic Chemistry, 3^(rd) Ed,Thomas L. Gilchrist, Addison-Wesley-Longman Ltd, 1997; An Introductionto the Chemistry of Heterocyclic Compounds, 3^(rd) Ed, R. M. Acheson,Wiley Interscience, 1976; etc, and references cited therein. Specificexamples of the General Method 4 include an Oxadiazole Process (Schemes4a and 4b), a Thiadiazole Process (Scheme 4c), and an Oxazole Process(Scheme 6 a-e). If necessary, the reaction can be carried out with abasic group synthon incorporated as the basic group, i.e., a group thatcould readily be converted to a basic group by methods known to oneskilled in the art. Basic group synthons would include, but not belimited to, halogen, protected amine, nitrile, aldehyde, and the like.Following the Heterocycle Formation Process, these groups would then beunmasked or converted under standard conditions to afford the basicgroup.

As outlined in Scheme 4a below, the coupling process of General Method 4can consist of a Oxadiazole Process. The diacylhydrazide compound ofFormula 51 is produced by acylation of an acylhydrazide of Formula 50(or Formula 53) by a carboxylic acid derivative of Formula 49 (orFormula 54). The acylation process is carried out in accordance with theabove Acylation/Sulfonylation Process of the General Method 2. Thediacylhydrazide is cyclized to the oxadiazole compounds of the inventionof Formula 52 utilizing dehydration processes analogous to thatdescribed in J Org Chem 1999, 64 (19), 6989–6992; and Chem HeterocyclCompd 1999, 35 (3), 275–280.

One equivalent of compound of Formula 51 is reacted with one toequivalents of a dehydrating agent in the presence, or absence, a basein an inert solvent. The reaction is normally carried out between 25° C.and 250° C. for between 4 to 72 hours. Examples of “dehydrating agents”include, SOCl₂, H₃PO₄, POCl₃, PCl₅, Tf₂O, Ac₂O, PPh₃-I₂, PPh₃—Br₂,PPh₃—Cl₂, PPh₃–CBr₄, PPh₃–CCl₄, PPA, NH(Tms)₂, P₂O₅, Me₂SiCl₂, PhOPCl₂,H₂SO₄, and the like.

As outlined in Scheme 4b below, an alternative Oxadiazole Process may beutilized to prepare the oxadiazole compounds of the invention of Formula52. The carboxylic acid derivative of Formula 49 (or 54) is activatedfor coupling as a “reactive acylating agent.” The acylation process iscarried out in accordance with the above Acylation/Sulfonylation Processof the General Method 2. The acylated intermediate is converted to theoxadiazole compounds of the invention of Formula 52. The process isanalogous to that described in Synth Commun 1994, 24 (11), 1575–1582; JOrg Chem 1961, 26, 2372; Synthetic Commun 24 (11), 1575–1582 (1994);etc, and references cited therein.

One to five equivalents of the “reactive acylating agent” of compound 49(or compound 54) and one to five equivalents of compound of Formula 55(or 57) are reacted in an inert solvent. If necessary the reaction canbe carried out in the presence of a one to five equivalents of1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and (or) acatalytic quantity to five equivalents of a base. The reactionintermediate of Formula 56 (or 58) may, or may not, be isolated. Thereaction is normally carried out between 0° C. and 200° C. Reaction timeis normally 4 to 48 hours. Reactive acylation agents have been describedand may similarly be prepared for compounds 49 and/or 55 as describedpreviously.

One equivalent of compound of Formula 51 is reacted with one to fiveequivalents of a thiol dehydrating agent in the presence, or absence, abase in an inert solvent. The reaction is normally carried out between25° C. and 250° C. for between 4 to 72 hours. Examples of “thioldehydrating agents” include, P₂S₅, Lawesson reagent, and the like.

General Method 5: Coupling of the Linker Group L¹

The compounds of Formula 3 can be prepared by the General Method 5,described in General Scheme 5, via reaction of the coupling group ofFormula 62 with a coupling group of Formula 63, where during the courseof the coupling reaction the coupling groups are retained, or lost, toform the linker L¹ between the 5-membered ring heterocyclic group andAr¹. Ar¹, L¹, AR², L², and basic group are defined as above. La isdefined as a group that when the coupling process occurs results in theformation of the linker L² defined above. Examples of the General Method5 are an Ether/Thioether Alkylation Process (Scheme 5a), anAcylation/Sulfonylation Process Process (Scheme 5b), anUrea/Thiourea/Guanadine Coupling Process (Scheme 5c1, 5c2, 5c3), anOrganometallic Process (Scheme 5d), and a Wittig-type Coupling (Scheme5e).

If necessary, the reactions below may be carried out with a basic groupsynthon incorporated as the basic group, as described previously.Following the Coupling of the Linker Group (L¹) Process, these groupswould then be unmasked or converted under standard conditions to affordthe basic group.

As outlined in Scheme 5a below, the coupling process of General Method 5can consist of a Ether/Thioether Alkylation Process. Nucleophilicdisplacement by an alcohol or thiol-containing compound of Formula 64(or Formula 68) with a compound of Formula 65 (or Formula 67) containinga leaving group affords the ether and thioether compounds of Formula 66of the invention. The processes are analogous to the process describedfor the General Method 2, described in Scheme 2a, and carried out inaccordance with the above method.

As outlined in Scheme 5b below, the coupling process of General Method 5can consist of an Acylation/Sulfonylation Process. Acylation orsulfonylation of an alcohol or amine compound of Formula 70 with acarboxylic acid or sulfonic acid compound of Formula 69, affords theester, amide, sulfonic ester, or sulfonamide compounds of Formula 71.Alternatively, acylation or sulfonylation of an alcohol or aminecompound of Formula 72 with a carboxylic acid or sulfonic acid compoundof Formula 73 affords the ester, amide, sulfonic ester, or sulfonamidecompounds of Formula 74. The processes are analogous to the processdescribed for the General Method 2, described in Scheme 2b, is carriedout in accordance with the above method.

As outlined in Schemes 5c1, 5c2, and 5c3, below, the coupling process ofGeneral Method 5 can consist of a Urea/Thiourea/Guanidine/Carbamate-TypeCoupling Process to afford the compounds of Formula 77, 81, and 84 ofthe invention. The processes are analogous to the processes describedfor the General Method 2, described in Schemes 2c1, 2c2, and 2c3, arecarried out in accordance with the above method.

As outlined in Schemes 5d below, the coupling process of General Method5 can consist of a Organometallic Coupling Process. The compound ofFormula 86 (or Formula 87) is coupled with an organometallic compound ofFormula 85 (or Formula 88) in an Organometallic Coupling Process toafford the compounds of Formula 3 of the invention. The processes areanalogous to the processes described for the General Method 2, describedin Scheme 2d, and are carried out in accordance with the above methods.

As outlined in Schemes 5e below, the coupling process of General Method2 can consist of a Wittig-type Coupling Process. The compound of Formula89 (or Formula 93) is coupled with the phosphorus ylene (or ylide)reagent of Formula 90 (Formula 92) to afford the compounds of Formula 91of the invention. The processes are analogous to the processes describedfor the General Method 2, described in Scheme 2e, and are carried out inaccordance with the above methods.

Preparation of Oxazole and Oxathiazole Compounds

As outlined in schemes 6a-c (below) the formation of oxazoles andthiazoles require elevated temperatures from 80–120° C. in solvents likedimethylformamide (scheme 6a+b) or phosphoryl chloride (scheme 6c).

These heterocyclic cyclisations result either in chloromethylsubstituted oxazoles and thiazoles (scheme 6a+c) or in vinyl substitutedoxazole (scheme 6b). After cis-hydroxylation of the later vinylsubstituted oxazole, followed by diol cleavage, as known to theartesian, the resulting formyl substituted oxazole can be converted viareduction and substitution to the chloro methyl substituted oxazole(scheme 6b). The cyclisation of □-bromoketone with acrylamide (scheme6b) is preferably performed in the presence of a stabiliser (such as 2,6di-tert.-butyl-4-methyl-phenol) to prevent polymerisation of theacrylamide. As outlined in scheme 6c, the condensation of 2-chloroacetyl chloride with an □-aminoketone in presence of a base such as, forexample, triethylamine, affords a product in high yield that can becyclised in phosphoryl chloride to result in formation of an oxazole.Unlike general scheme 4, these heterocyclic formations of oxazoles andthiazoles do not work as desired in the presence of Ar¹-L¹- nor in thepresence of -L²-basic group, so that these groups have to be introducedlater, as outlines in schemes 6d and 6e.

In order to achieve formation of the linker L¹, the chloromethylsubstituted oxazoles or thiazoles from scheme 6a-c can be used asalkylation substrates for thiolates (scheme 6d). Therefore, a thiol istreated with a base, like sodium ethoxide in ethanol, before addition ofthe chloro methyl substituted oxazole. This alkylation proceeds in thepresence of an unprotected phenol. The unprotected phenol can beincorporated into linker L² in a subsequent reaction, as outlined inscheme 6e in solvents such as dimethylformamide and involving bases suchas potassium carbonate. As outlined in scheme 6d, the phenol may beobtained from the Lewis-acid mediated cleavage of a methylether withLewis-acids, preferably, borontribromide in solvents such asdichloromethane.

For compounds wherein AR² is oxazole, positional isomers of the oxazolegroup (e.g isoxazole) may be made as shown in Scheme 7.

4-Hydroxy-benzaldehyde is protected as the tetrahydropyran (THP) ether,using dihydropyran and p-toluenesulfonic acid (PPTS) in dichloromethane.The aldehyde functionality is converted to an oxime with hydroxylaminehydrochloride and sodium acetate in ethanol. The oxine is then convertedto a chloro-oxime with NCS in DMF. Dipolar cycloaddition of thechloro-oxime and 3-chloropropyne in ethyl acetate using DIPEA ascatalyst gives the intermediate5-chloromethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole. Thisis then used to alkylate 2-phenoxy-ethanethiol. This intermediate isdeprotected with PPTS to give4-[5-(2-phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-phenol. The phenolis alkyated with 1-(2-chloro-ethyl)-pyrrolidine hydrochloride to givethe final product,5-(2-phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoxazole.

The 1,2,4-oxadiazole simer may be prepared following the procedure ofScheme as shown in Scheme 8 for the particular example.

As shown, 4–Cyanophenol is protected as the Tetrahydropyran (THP) etherusing dihyropyran and dihydropyran and p-toluenesulfonic acid (PPTS) indichloromethane. The cyano functionality is converted to an amidoximefunctionality by reaction with hydroxylamine hydrochloride and NaOH inethanol in a microwave chamber at 80 C. A mixture of the amidoxime and(2-phenoxy-ethylsulfanyl)-acetyl chloride in pyridine is microwaved at80 C to give the isoxazole intermediate as a mixture of protected THPether and deprotected phenol. After removal of pyridine under vacuum,the reaction products are treated with PPTS in ethanol and microwaved at75 C to deprotect any remaining THP ether, giving4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol. Thephenol is alkyated with 1-(2-chloro-ethyl)-pyrrolidine hydrochloride togive the final product,5-(2-phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]oxadiazolehydrochloride.One of skill in the art is aware that other compounds within the scopeof the invention may be made as shown or by modifications to theprocedures provided which are not cumbersome and are known to one ofskill in the art or accessible in the general reference texts orliterature available to one of skill in the art. Futhermore, in additionto the discussive procedures herein, detailed examples are providedwhich would further assist one of skill in the art to make theappropriate modifications to arrive at compounds within the scope thatare not specifically exemplified.

Demonstration of Function

In order to demonstrate that compounds of the present invention have thecapacity to bind to and inhibit the function of MCHR1, binding andfunctional assays were established. All ligands, radioligands, solventsand reagents employed in these assays are readily available fromcommercial sources or can be readily prepared by those skilled in theart.

The full-length cDNA for human MCHR1 was cloned from a human adult braincDNA library (Edge Biosystems, Cat. 38356) by standard polymerase chainreaction (PCR) methodology employing the following primers: sense,5′-GCCACCATGGACCT GGAAGCCTCGCTGC-3′; anti-sense,5′-TGGTGCCCTGACTTGGAGGTGTGC-3′.

The PCR reaction was performed in a final volume of 50 μl containing 5μl of a 10× stock solution of PCR buffer, 1 μl of 10 mM dNTP mixture(200 μM final), 2 μl of 50 mM Mg(SO₄) (2 mM final), 0.5 μl of 20 μMsolutions of each primer (0.2 μM final), 5 μl of template cDNAcontaining 0.5 ng DNA, 0.5 μl of Platinum Taq High Fidelity DNApolymerase (Gibco Life Technologies) and 36 μl of H₂O. PCR amplificationwas performed on a Perkin Elmer 9600 thermocycler. After denaturationfor 90 sec at 94° C., the amplification sequence consisting of 94° C.for 25 sec, 55° C. for 25 sec and 72° C. for 2 min was repeated 30times, followed by a final elongation step at 72° C. for 10 min. Thedesired PCR product (1.1 Kb) was confirmed by agarose gelelectrophoresis and the band was extracted from the gel by Geneclean(Bio 1) following the manufacturer's instructions. Following extraction,the cDNA fragment was cloned into pCR2.1-TOPO plasmid (Invitrogen) toconfirm the identity and sequence.

In order to generate cell lines stably expressing MCHR1, the insert wasthen subcloned into the Xba I and Not I sites of pcDNA(+)-3.1-neomycin(Invitrogen). After purification by Qiagen Maxi-prep kit (QIAGEN, Inc.),the plasmid was transfected by Fugene 6 (Roche Applied Science) intoAV12 cells that had been previously transfected with the promiscuous Gprotein G_(α15). The transfected cells were selected by

G418 (800 μg/ml) for 10–14 days and single colonies were isolated fromculture plates. The G418-resistant colonies were further selected forMCHR1 expression by measuring MCH-stimulated Ca transients with afluorometric imaging plate reader (FLIPR, Molecular Devices).

Typically, individual clones are plated out in 96-well plates at 60,000cells per well in 100 μl of growth medium (Dulbecco's modified Eagle'smedium (DMEM), 5% fetal bovine serum, 2 mM L-glutamine, 10 mM HEPES, 1nmM sodium pyruvate, 0.5 mg/ml Zeocin, and 0.5 mg/ml Geneticin). After24 hrs at 37° C., medium is removed and replaced with 50 μl of dyeloading buffer (Hank's balanced salt solution (HBSS) containing 25 mMHEPES, 0.04% Pluronate 127 and 8 μM Fluo3 Both from Molecular Probes)).After a 60 min loading period at room temperature, dye loading buffer isaspirated and replaced with 100 μl of HEPES/HBBS. Plate is placed inFLIPR and basal readings are taken for 10 sec, at which point 100 μl ofbuffer containing 2 μM MCH (1 μM final) is added and measurements aretaken over 105 sec. To correct for variations between clones in numbersof cells per well, the MCH response is normalized to the responseinduced by epinephrine.

Both the ¹²⁵I-MCH binding and functional GTPγ³⁵S binding assays employedmembranes isolated from a clone designated as clone 43. Typically, cellsfrom 20 confluent T225 flasks were processed by washing the monolayersin cold phosphate-buffered saline (PBS), scraping the cells into sameand re-suspending the cell pellet in 35 ml of 250 mM Sucrose, 50 mMHEPES, pH 7.5, 1 mM MgCl₂, 24 μg/ml DNase I, and protease inhibitors (1Complete® tablet, per 50 ml of buffer prepared, Roche Diagnostics).After incubation on ice for 5 min, cells were disrupted with 20–25strokes of a Teflon/Glass homogenizer attached to an overhead motorizedstirrer, and the homogenate was centrifuged at 40,000 rpm in BeckmanType 70.1 Ti rotor. The pellets were re-suspended in 250 mM Sucrose, 50mM HEPES, pH 7.5, 1.5 mM CaCl₂, 1 mM MgSO₄ and protease inhibitors byTeflon/Glass homogenization to achieve a protein concentration of ˜3–5mg/ml (Pierce BCA assay with Bovine serum albumin as standard).

Aliquots were stored at −70° C. Binding of compounds to MCHR1 wasassessed in a competitive binding assay employing ¹²⁵I-MCH, compound andclone 43 membranes. Briefly, assays are carried out in 96-well Costar3632 white opaque plates in a total volume of 200 μl containing 25 mMHEPES, pH 7.5, 10 mM CaCl₂, 2 mg/ml bovine serum albumin, 0.5% dimethylsulfoxide (DMSO), 4 μg of clone 43 membranes, 100 μM ¹²⁵I-MCH (NEN), 1.0mg of wheat germ agglutinin scintillation proximity assay beads (WGA-SPAbeads, Amersham) and a graded dose of test compound. Non-specificbinding is assessed in the presence of 1 μM unlabeled MCH. Bound¹²⁵I-MCH is determined by placing sealed plates in a Microbeta Trilux(Wallac) and counting after a 5 hr delay.

IC₅₀ values (defined as the concentration of test compound required toreduce specific binding of ¹²⁵I-MCH by 50%) are determined by fittingthe concentration-response data to a 4-parameter model (max response,min response, Hill coefficient, IC₅₀) using Excel. K_(i) values arecalculated from IC₅₀ values using the Cheng-Prusoff approximation asdescribed by Cheng et al. (Relationship between the inhibition constant(K_(i)) and the concentration of inhibitor which causes 50% inhibition(IC₅₀) of an enzymatic reaction, Biochem. Pharmacol., 22: 3099–3108(1973)). The K_(d) for ¹²⁵I-MCH is determined independently from asaturation binding isotherm.

Functional antagonism of MCH activity is assessed by measuring theability of test compound to inhibit MCH-stimulated binding of GTPγ³⁵S toclone 43 membranes. Briefly, assays are carried out in Costar 3632 whiteopaque plates in a total volume of 200 μl containing 25 mM Hepes, pH7.5, 5 mM MgCl₂, 10 μg/ml saponin, 100 mM NaCl, 3 μM GDP, 0.3 nMGTPγ³⁵S, 40 nM MCH (approximately equal to EC₉₀), 20 μg of clone 43membranes, 1.0 mg of wheat germ agglutinin scintillation proximity assaybeads (WGA-SPA beads, Amersham) and a graded dose of test compound. Theplates are sealed and left for 16–18 hrs at 4° C. After a 1 hr delay toallow plates to equilibrate to ambient temperature, bound GTPγ³⁵S isdetermined by counting in a Microbeta Trilux (Wallac).

IC₅₀ values (defined as the concentration of test compound required toreduce MCH-stimulated GTPγ³⁵S binding by 50%) are determined by fittingthe concentration-response data to a 4-parameter model (max response,min response, Hill coefficient, IC₅₀) using Excel. K_(b) values arecalculated from IC₅₀ values using a modification of the Cheng-Prusoffapproximation as described by Leff and Dougal (Further concerns overCheng-Prusoff analysis, Trends Pharmacol. Sci. 14: 110–112 (1993)) afterverifying competitive antagonism by Schild analysis. The EC₅₀ for MCHalone is determined independently. The MCHR1 binding and functionalactivities of 24 compounds in the oxadiazole series (tested induplicate) are shown in Table 1

TABLE 1 Structure K_(i) (nM) K_(b) (nM)

1.9 6.0

3.7 11.6

4.3 15.0

5.3 13.6

5.6 14.7

5.8 12.0

9 20.0

9.2 19.8

10.2 16.5

10.4 16.2

11.6 7.3

12.9 39.6

13.3 9.4

14.3 18.1

16 11.9

16.1 35.4

17.9 15.9

22.4 50.6

35 41.5

37.9 31.3

48.4 139.5

63.3 52.1

140 145.2

2898 6889

In order to demonstrate in vivo efficacy of this series of compounds,compound of example 136 was injected intracerebro-ventricularly in theabsence or presence of 2.1 nmol MCH, and its ability to block the effectof exogenous MCH was assessed. Diet-induced obese male Long-Evans rats(Harlan, Ind.) weighing 500–550 g at time of surgery were anesthetizedwith isoflurane. Stainless steel cannula guides (5 mm length, 26 gauge,Plastics One, Va.) were stereotaxically implanted in the lateralventricle anteroposteriority: 0.8 mm caudal to bregma; and lateral: 1.5mm from midline suture. Animals were individually housed in atemperature regulated room (24° C.) with a reverse 12 hour light/darkcycle (dark 10:00/22:00). Water and food (Teklad 95217, Harlan, Wis.)were available ad libitum. After surgery, animals were allowed torecover 7 days before experimental use. On test day, food was removed 1hr prior to testing and animals (4 groups, n=6 per group) were injectedbetween 0900 and 1000 with 5 μl of vehicle (artificial CSF), 2.1 nmolMCH, 82 nmol of compound of example 136, and MCH plus compound ofexample 136. Cumulative food intake was measured at 2, 4 and 6 hoursafter injection. The results are shown in FIG. 1. Treatment withcompound of example 136 completely blocked the orexigenic effect ofexogenous MCH (*p<0.05 vs. MCH alone).

Utility

As antagonists of the MCHR1 binding, a compound of the present inventionis useful in treating conditions in human and non-human animals in whichthe the MCHR1 receptor has been demonstrated to play a role. Thediseases, disorders or conditions for which compounds of the presentinvention are useful in treating or preventing include, but are notlimited to, diabetes mellitus, hyperglycemia, obesity, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, atherosclerosis of coronary,cerebrovascular and peripheral arteries, gastrointestinal disordersincluding peptid ulcer, esophagitis, gastritis and duodenitis,(including that induced by H. pylori), intestinal ulcerations (includinginflammatory bowel disease, ulcerative colitis, Crohn's disease andproctitis) and gastrointestinal ulcerations, neurogenic inflammation ofairways, including cough, asthma, depression, prostate diseases such asbenign prostate hyperplasia, irritable bowel syndrome and otherdisorders needing decreased gut motility, diabetic retinopathy,neuropathic bladder dysfunction, elevated intraocular pressure andglaucoma and non-specific diarrhea dumping syndrome. By inhibiting theMCH activity the compounds of the invention provide anorexic effects.That is, the compounds of the invention are useful as appetitesuppressants and/or weightless agents. Compounds of the presentinvention have also shown some affinity for the R2 isoform of MCHR. Thecompounds of the invention may also be used in combination with otherapproved therapeutic agents for the treatment and/or prevention ofobesity and related diseases. In this format, the compounds of thepresent invention enhance the positive effects of such combinationtreatments while minimizing the side effects due to the potentialrequirement of lower doses of such combination compounds. Suchcombination therapies may be delivered individually or in a combinedformulation. Examples of compounds potentially useful in combinationwith compounds of formula I include weight loss agents (Mevidia™,Xenical™), cholesterol lowering agents, glucose level control ormodulating agents and the like.

In treating non-human, non-companion animals, the compounds of thepresent invention are useful for reducing weight gain and/or improvingthe feed utilization efficiency and/or increasing lean body mass.

Formulation

The compound of formula I is preferably formulated in a unit dosage formprior to administration. Therefore, yet another embodiment of thepresent invention is a pharmaceutical formulation comprising a compoundof formula I and a pharmaceutical carrier.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (formula Icompound) will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a liquid,tablet, capsule, sachet, paper or other container. When the carrierserves as a diluent, it may be a solid, semisolid or liquid materialwhich acts as a vehicle, excipient or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosol (as a solid or in a liquid medium), soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

FORMULATION EXAMPLES

Formulation 1 Tablets Ingredient Quantity (mg/tablet) Active Ingredient5–500 Cellulose, microcrystalline 200–650  Silicon dioxide, fumed10–650  Stearate acid 5–15 The components are blended and compressed to form tablets.

Formulation 2 Suspensions Ingredient Quantity (mg/5 ml) ActiveIngredient 5–500 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mgBenzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to 5mlThe medicament is passed through a No. 45 mesh U.S. sieve (approximately355 micron opening) and mixed with the sodium carboxymethyl celluloseand syrup to form a smooth paste. The benzoic acid solution, flavor, andcolor are diluted with some of the water and added, with stirring.Sufficient water is then added to produce the required volume.

Formulation 3 Intravenous Solution Ingredient Quantity Active Ingredient25 mg Isotonic saline 1,000 mlThe solution of the above ingredients is intravenously administered to apatient at a rate of about 1 ml per minute.Dose

The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age and sex of the recipient.However, it will be understood that the therapeutic dosage administeredwill be determined by the physician in the light of the relevantcircumstances, or by the vetrinarian for non-human recipients.

Generally, an effective minimum daily dose of a compound of formula I isabout 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about500, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 5 mgand 60 mg. The exact dose may be determined, in accordance with thestandard practice in the medical arts of “dose titrating” the recipient;that is, initially administering a low dose of the compound, andgradually increasing the does until the desired therapeutic effect isobserved.

Route of Administration

The compounds may be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, topical, intravenous,intramuscular or intranasal routes.

Combination Therapy

A compound of formula I may be used in combination with other drugs ortherapies that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds offormula I are useful. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalunit dosage form containing such other drugs in addition to the compoundof formula I is preferred. Accordingly, the pharmaceutical compositionsof the present invention include those that also contain one or moreother active ingredients, in addition to a compound of formula I.Examples of other active ingredients that may be combined with acompound of formula I, either administered separately or in the samepharmaceutical compositions, include, but are not limited to:

-   -   (a) insulin sensitizers including (i) PPARγ agonists such as the        glitazones (e.g. troglitazone, pioglitazone, englitazone,        MCC-555, BRL49653 and the like), and compounds disclosed in        WO97/27857, 97/28115, 97/28137 and 97/27847;        -   (ii) biguanides such as metformin and phenformin;    -   (b) insulin or insulin mimetics;    -   (c) sulfonylureas such as tolbutamide and glipizide;    -   (d) alpha-glucosidase inhibitors (such as acarbose);    -   (e) cholesterol lowering agents such as        -   i. HMG-CoA reductase inhibitors (lovastatin, simvastatin and            pravastatin, fluvastatin, atorvastatin, and other statins),        -   ii. sequestrants (cholestyramine, colestipol and a            dialkylaminoalkyl derivatives of a cross-linked dextran),        -   iii. nicotinyl alcohol nicotinic acid or a salt thereof,        -   iv. proliferator-activator receptor a agonists such as            fenofibric acid derivatives (gemfibrozil, clofibrat,            fenofibrate and benzafibrate),        -   v. inhibitors of cholesterol absorption for example            P-sitosterol and (acyl CoA:cholesterol acyltransferase)            inhibitors for example melinamide,        -   vi. probucol,        -   vii. vitamin E, and        -   viii. thyromimetics;    -   (f) PPARδ agonists such as those disclosed in WO97/28149;    -   (g) antiobesity compounds such as fenfluramine, dexfenfluramine,        phentermine, sibutramine, orlistat, and other P3 adrenergic        receptor agonists;    -   (h) feeding behavior modifying agents such as neuropeptide Y        antagonists (e.g. neuropeptide Y5) such as those disclosed in WO        97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;    -   (i) PPARα agonists such as described in WO 97/36579 by Glaxo;    -   (j) PPARγ antagonists as described in WO97/10813; and    -   (k) serotonin reuptake inhibitors such as fluoxetine and        sertraline    -   (l) antipsychotic agents such as for example olanzapine.

EXAMPLES

The following examples are only illustrative of the prepration protocolsand Applicants' ability to prepare compounds of the present inventionbased on the schemes presented or modifications thereof. The examplesare not intended to be exclusive or exhaustive of compounds made orobtainable.

Example 1 Preparation ofN-(3-Dimethylaminopropyl)-4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 3-phenyl-1-propanol

a) (3-Phenylpropoxy)acetic acid

To a solution of 3-phenyl-1-propanol (5.0 g, 36.7 mmol) in 36 mL THF atroom temperature was added, in portions, sodium hydride (1.54 g, 38.5mmol). After 30 minutes, a solution of methyl bromoacetate (6.18 g, 40.4mmol) in 18 mL THF was added and the resultant mixture stirred at roomtemperature for 4.1 hours. Next, the mixture was diluted with 20 mL H₂O,then lithium hydroxide (2.64 g, 110 mmol) was added and the biphasicsolution was heated at 60° C. for 1.5 hours. The mixture was then cooledto room temperature, diluted with Et₂O and washed three times with H₂O.The combined aqueous phases were acidified with concentrated HCl untilpH<2. The resultant mixture was extracted three times with Et₂O. Theorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated to afford an oil. Purification by flashfiltration chromatography on silica gel (elution with CH₂Cl₂ followed by9:1 CH₂Cl₂:MeOH) afforded 2.7 g (38%) of(3-phenylpropoxy)acetic acid asan oil.

¹HNMR (DMSO-d6) δ 7.30–7.15 (m, 5H), 3.99 (s, 2H), 3.5 (t, 2H, J=6 Hz),2.63 (t, 2H, J=7 Hz), 1.76–1.85 (m, 2H). IR (CHCl₃, cm⁻¹) 3027, 3019,3013, 2948, 1779, 1732, 1454, 1246, and 1136.MS (ES) m/e 193. Anal.Calcd for C₁₁H₁₄O₃: C, 68.02; H, 7.27. Found C, 68.58; H, 6.91

b) 4-[5-(3-Phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester

To a solution of (3-phenylpropoxy)acetic acid (1.11 g, 5.7 mmol) in 14.6mL toluene at room temperature was added 1,3-dicyclohexylcarbodiimide(1.11 g, 5.7 mmol). After five minutes, 4-(1H-tetrazole-5-yl)benzoicacid methyl ester (1.16 g, 5.7 mmol) was added and the suspension washeated at 100° C. for thirty minutes, then at 130° C. for thirtyminutes. The mixture was cooled to room temperature then diluted withCH₂Cl₂ and filtered. Concentration of the filtrate afforded a solid.Purification by radial chromatography on silica gel (elution with 50%EtOAc:hexane) followed by crystallization of the isolated material fromEt₂O:hexane afforded 0.921 g (46%) of4-[5-(3-Phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester.

¹HNMR (DMSO-d6) δ 8.17 (s, 4H), 7.1–7.3 (m, 5H), 4.8 (s, 2H), 3.9 (s,3H), 3.6 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=8 Hz), 1.8–1.9 (m, 2H). IR(CHCl₃, cm⁻¹) 1722, 1438, 1283, 1111. MS (ES) m/e 353. Anal. Calcd forC₂₀H₂₀N₂O₄: C, 68.17; H, 5.72; N, 7.95. Found C, 67.78; H, 5.69; N,7.74.

c) 4-[5-(3-Phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid

A mixture of 4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester (0.866 g, 2.5 mmol) and lithium hydroxide (0.177 g,7.4 mmol) in 3.85 mL THF and 1.65 mL H₂O was stirred at 60° C. for 1hour. Upon cooling to room temperature the mixture was acidified withconcentrated HCl (0.421 mL) and reduced in volume to remove the THF. Theresulting insoluble material was collected by filtration to afford 0.760g (91%) of 4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid.

¹H NMR (DMSO-d6)

8.1 (m, 4H), 7.1–7.3 (m, 5H), 4.8 (s, 2H), 3.6 (t, 2H, J=6 Hz) 2.6 (t,2H, J=7 Hz), 1.8–1.9 (m, 2H). IR (CHCl₃, cm⁻¹) 3097, 3028, 2944, 2856,2675, 2559, 1706, 1685, 1583, 1551, 1433, 1292, 1108, 874, 719. MS (ES)m/e 339, 337 Anal. Calcd for C₁₉H₁₈N₂O₄: C, 67.45; H, 5.36; N, 8.28.Found C, 66.34; H, 5.31; N, 8.18.

d)N-(3-Dimethylaminopropyl)-4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamide

A mixture of 4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid (0.730 g, 2.2 mmol) and 1,1′-carbonyldi-imidazole (0.367 g, 2.3mmol) was stirred in 18 mL THF at 60° C. for 45 minutes. After stirringan additional 45 minutes at room temperature,3-(dimethylamino)propylamine (0.265 g, 2.59 mmol) was added. Afterstirring approximately 24 h at room temperature, the mixture wasconcentrated to an oil. The oil was treated with Et₂O and the resultantsuspension was filtered. The filtrate was treated with hexane and theresultant crystals were collected by filtration to afford 0.451 g (49%)ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6) δ 8.7 (d, 1H, J=5 Hz), 8.1 (d, 2H, J=8 Hz), 8.0 (d, 2H,J=8 Hz), 7.1–7.3 (m, 5H), 4.8 (s, 2H), 3.5 (t, 2H, J=6 Hz), 3.32 (m,2H), 2.62 (t, 2H, J=7 Hz), 2.27 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.86 (m,2H), 1.67 (m, 2H). MS (ES) m/e, 423, 421. Anal. Calcd for C₂₄H₃₀N₄O₃: C,68.22; H, 7.16; N, 13.26. Found C, 67.89; H, 7.09; N, 13.15. Mp(°C.)=90.

Example 2N-(3-Dimethylaminopropyl)-4-[5-(2-phenethyloxyethyl)-[1,3,4-oxadiazol-2-yl]benzamidefrom 3-Phenethyloxypropionic acid

a) 4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 3-Phenethyloxypropionic acid(1.02 g, 5.3 mmol), 1,3-dicyclohexylcarbodiimide (1.08 g, 5.3 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.06 g, 5.2 mmol) toafford 0.79 g (43%) of4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester as a crystalline solid.

¹HNMR (DMSO-d6)

8.09–8.18 (m, 4H), 7.07–7.17 (m, 5H), 3.91 (s, 3H), 3.85 (t, 2H, J=6Hz), 3.65 (t, 2H, J=7 Hz), 3.20 (t, 2H, J=6 Hz), 2.78 (t, 2H, J=7 Hz).IR (CHCl₃, cm⁻¹) 3009, 2954, 2871, 1721, 1438, 1282, 1111. MS (ES) m/e,353. Anal. Calcd for C₂₀H₂₀N₂O₄: C, 68.17; H, 5.72; N, 7.95. Found C,68.38; H, 5.66; N, 8.01.

b) 4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester 0.724 g, 2.1 mmol) and lithium hydroxide (0.148 g, 6.2 mmol) toafford 0.558 g (80%) of4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid as solid.

¹H NMR (DMSO-d6)

8.05–8.16 (m, 4H), 7.07–7.17 (m, 5H), 3.85 (t, 2H, J=6 Hz), 3.65 (t, 2H,J=7 Hz), 3.20 (t, 2H, J=6 Hz), 2.78 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹)3431, 1705, 1685, 1434, 1290, 1118, 715. MS (ES) m/e, 339, 337. Anal.Calcd for C₁₉H₁₈N₂O₄: C, 67.45; H, 5.36; N, 8.28. Found C, 64.37; H,5.08; N, 9.05.

c)N-(3-Dimethylaminopropyl)-4-[5-(2-phenethyloxyethyl)-[1,3,4-oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(2-Phenethyloxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid (0.528 g,1.6 mmol), 1,1′-carbonyldiimidazole (0.266 g, 1.6 mmol) and3-(dimethylamino)propylamine (0.392 g, 3.8 mmol) to afford 0.309 g (47%)ofN-(3-Dimethylaminopropyl)-4-[5-(2-phenethyloxyethyl)-[1,3,4-oxadiazol-2-yl]benzamideas a crystalline solid.

¹H NMR (DMSO-d6)

8.71 (t, 1H, J=5 Hz), 8.05 (d, 2H, J=9 Hz), 8.02 (d, 2H, J=9 Hz),7.09–7.17 (m, 5H), 3.85 (t, 2H, J=9 Hz), 3.65 (t, 2H, J=7 Hz), 3.29 (m,2H), 3.19 (t, 2H, J=6 Hz), 2.78 (t, 2H, J=7 Hz), 2.26 (t, 2H, J=7 Hz),2.14 (s, 6H), 1.66 (m, 2H). IR (CHCl₃, cm⁻¹) 3307, 2942, 2879, 2761,1631, 1540, 1116, 858, 699. MS (ES) m/e, 423, 421. Anal. Calcd forC₂₄H₃₀N₄O₃: C, 68.22; H, 7.16; N, 13.26. Found C, 67.83; H, 7.24; N,13.19. Mp(° C.)=92.

Example 3 Preparation of4-[5-(3-Benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3dimethylaminopropyl)benzamide from 4-benzyloxybutyric acid

a)4-[5-(3-Benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 4-benzyloxybutyric acid (0.725g, 3.7 mmol), 1,3-dicyclohexylcarbodiimide (0.771 g, 3.7 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.755 g, 3.7 mmol) toafford 0.733 g (56%) of4-[5-(3-benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoicacid methyl ester as a crystalline solid.

¹HNMR (DMSO-d6)

8.09–8.16 (m, 4H), 7.23–7.30 (m, 5H), 4.46 (s, 2H), 3.90 (s, 3H), 3.56(t, 2H, J=6 Hz), 3.03 (t, 2H, J=7 Hz), 2.07 (m, 2H). IR (CHCl₃, cm⁻¹)1721, 1438, 1282, 1111. MS (ES) m/e, 353. Anal. Calcd for C₂₀H₂₀N₂O₄: C,68.17; H, 5.72; N, 7.95. Found C, 68.10; H, 5.79; N, 8.03.

b)4-[5-(3-Benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(3-benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoic acid methyl ester (0.669 g, 1.9 mmol) and lithiumhydroxide (0.136 g, 5.7 mmol) to afford 0.610 g (95%)4-[5-(3-benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoicacid as a solid.

¹H NMR (DMSO-d6) δ 8.06–8.14 (m, 4H), 7.23–7.29 (m, 5H), 4.46 (s, 2H),3.56 (t, 2H, J=6 Hz), 3.03 (t, 2H, J=7 Hz), 2.02–2.11 (m, 2H). IR (KBr,cm⁻¹) 2859, 1681, 1428, 1321, 1292, 1119, 720. MS (ES) m/e, 339, 337.Anal. Calcd for C₁₉H₁₈N₂O₄: C, 67.45; H, 5.36; N, 8.28. Found C, 67.15;H, 5.36; N, 8.32.

c)4-[5-(3-Benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from(4-[5-(3-Benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzoic acid (0.580 g, 1.7 mmol), 1,1′-carbonyl diimidazole(0.291 g, 1.8 mmol) and 3-(dimethylamino)propyl amine (0.210 g, 2.1mmol) to afford 0.408 g (56%)4-[5-(3-benzyloxypropyl)-[1,3,4]oxadiazol-2-yl]-N-(3-dimethylaminopropyl)benzamide as a crystalline material.

¹H NMR (DMSO-d6) 68.69 (m, 1H), 7.99–8.07 (m, 4H), 7.28 (m, 5H), 4.46(s, 2H), 3.55 (t, 2H, J=6 Hz), 3.30 (m, 2H), 3.02 (t, 2H, J=7 Hz), 2.26(t, 2H, J=7 Hz), 2.14 (s, 6H), 2.06 (m, 2H), 1.66 (m, 2H). IR (CHCl₃,cm⁻¹) 3008, 2864, 2827, 1651, 1587, 1556, 1494, 1093. MS (ES) m/e, 423,421. Anal. Calcd for C₂₄H₃₀N₄O₃: C, 68.22; H, 7.16; N, 13.26. Found C,67.24; H, 6.01; N, 12.84. Analytical HPLC: 100% purity. Mp(° C.)=106

Example 4 Preparation ofN-(3-Dimethylaminopropyl)4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 5-phenoxypentanoic acid

a) 4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 5-phenoxypentanoic acid (1.02 g,5.3 mmol), 1,3-dicyclohexylcarbodiimide (1.08 g, 5.3 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.06 g, 5.2 mmol) toafford 0.639 g (38%) of4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester asa crystalline material.

¹HNMR (DMSO-d6)

8.10 (m, 4H), 7.23–7.29 (m, 2H), 6.88–6.94 (m, 3H), 4.02 (t, 2H, J=6Hz), 3.90 (s, 3H), 3.04 (t, 2H, J=7 Hz), 1.83–1.98 (m, 4H). IR (CHCl₃,cm⁻¹) 1721, 1587, 1498, 1438, 1283, 1245, 1111. MS (ES) m/e, 353. Anal.Calcd for C₂₀H₂₀N₂O₄: C, 68.17; H, 5.72; N, 7.95. Found C, 67.89; H,5.58; N, 7.91.

b) 4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester(0.560 g, 1.6 mmol) and lithium hydroxide (0.114 g, 4.8 mmol) to afford0.491 g (91%) of 4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoicacid as a solid.

¹H NMR (DMSO-d6)

8.08–8.15 (m, 4H), 7.23–7.30 (m, 2H), 6.88–6.94 (m, 3H), 4.02 (t, 2H,J=6 Hz), 3.04 (t, 2H, J=7 Hz), 1.81–2.00 (m, 4H). IR (KBr, cm⁻¹) 1684,1585, 1501, 1321, 1292, 1256, 723. MS (ES) m/e, 339, 337. Anal. Calcdfor C₁₉H₁₈N₂O₄: C, 67.45; H, 5.36; N, 8.28. Found C, 66.79; H, 5.40; N,8.27.

c)N-(3-Dimethylaminopropyl)4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzoic acid (0.461 g, 1.4mmol), 1,1′-carbonyldiimidazole (0.231 g, 1.4 mmol) and3-(dimethylamino)propylamine (0.167 g, 1.6 mmol) to afford the titlecompound as a crude mixture. Crystallization of the material from EtOAcafforded 0.237 g (40%) ofN-(3-dimethyl-aminopropyl)4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.70 (m, 1H), 8.00–8.08 (m, 4H), 7.23–7.30 (m, 2H), 6.88–6.94 (m, 3H),4.02 (t, 2H, J=6 Hz), 3.32 (m, 2H), 2.26 (t, 2H, J=7 Hz), 2.14 (s, 6H),1.83–1.98 (m, 4H), 1.62–1.72 (m, 2H). IR (KBr, cm⁻¹) 3310, 2953, 2763,1634, 1563, 1540, 1498, 1253, 1249, 1010, 855, 749. MS (ES) m/e, 423,421. Anal. Calcd for C₂₄H₃₀N₄O₃: C, 68.22; H, 7.16; N, 13.26. Found C,68.25; H, 7.21; N, 12.82. Analytical HPLC: 100% purity. Mp(° C.)=114.

Example 5 Preparation ofN-(Dimethylaminopropyl)4-[5-(2-phenoxy-ethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 2-phenoxyethanol

a) 2-(Phenoxyethoxy)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1a, from 2-phenoxyethanol (5.4 g, 38.9mmol) and methyl bromoacetate (6.55 g, 42.8 mmol), then, using lithiumhydroxide (2.78 g 116.1 mmol) to afford 5.9 g (77%) of2-(phenoxyethoxy)acetic acid as an oil.

¹H NMR (DMSO-d6)

7.25–7.31 (m, 2H), 6.93 (m, 3H), 4.11 (m, 4H), 3.81 (m, 2H). IR (CHCl₃,cm⁻¹) 1733, 1600, 1589, 1498, 1245, 1144. MS (S) m/e, 197, 195. Anal.Calcd for C₁₀H₁₂O₄: C, 61.22; H, 6.16. Found C, 61.49; H, 5.70.

b) 4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 2-(phenoxyethoxy)acetic acid(1.08 g, 5.5 mmol), 1,3-dicyclohexylcarbodiimide (0.957 g, 4.6 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.938 g, 4.6 mmol) toafford 0.559 g (35%) of4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester as a crystalline solid contaminated with 1,3-dicyclohexylurea.

¹H NMR (DMSO-d6)

8.15 (m, 4H), 7.22–7.29 (m, 2H), 6.89–6.94 (m, 3H), 4.92 (s, 2H), 4.15(m, 2H), 3.92–4.17 (m, 2H), 3.91 (s, 3H). IR (CHCl₃, cm⁻¹) 3328, 2850,1719, 1601, 1565, 1441, 1296, 1282, 1254, 1146, 1137, 1112, 759, 715. MS(ES) m/e,

-   -   355. Anal. Calcd for Cl₉H₁₈N₂O₅: C, 64.40; H, 5.12; N, 7.91.        Found C, 64.72; H, 5.66; N, 8.37.

c) 4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methylester (0.500 g, 1.4 mmol) and lithium hydroxide (0.101 g, 4.2 mmol) toafford 0.366 g (76%) as a solid contaminated with 1,3-dicyclohexylurea

¹H NMR DMSO-d6)

7.95–8.06 (m, 4H), 7.26–7.32 (m, 2H), 6.91–6.98 (m, 3H), 4.14–4.19 (m,4H), 3.88 (m, 2H).

IR (KBr, cm⁻¹) 3327, 2928, 2850, 1700, 1685, 1625, 1608, 1246, 1132,691. MS (ES) m/e, 339. Anal. Calcd for C₁₈H₁₆N₂O₅: C, 63.53; H, 4.74; N,8.23. Found C, 61.01; H, 5.65; N, 8.32.

d)N-(Dimethylaminopropyl)4-[5-(2-phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid 0.333 g,0.98 mmol), 1,1′-carbonyldiimidazole (0.160 g, 0.99 mmol) and3-(dimethylamino)propylamine (0.099 g, 1.0 mmol) to afford the titlecompound as a crude mixture. Purification by radial chromatography onsilica gel (eluted with 10% 2M NH₃ in MeOH:CHCl₃) afforded 0.03 g (7%)of N-(dimethylaminopropyl)4-[5-(2-phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]benzamide as asolid.

¹H NMR (DMSO-d6)

8.72 (t, 1H, J=5 Hz), 8.01–8.10 (m, 4H), 7.23–7.29 (m, 2H), 6.89–6.96(m, 3H), 4.19 (s, 2H), 4.15 (m, 2H), 3.93 (m, 2H), 3.31 (m, 2H), 2.26(t, 2H, J=7 Hz), 2.14 (s, 6H), 1.62–1.72 (m, 2H) IR (CHCl₃, cm⁻¹) 4446,2936, 2763, 1637, 1530, 1490, 1253, 1047, 752. MS (ES) m/e, 425, 423.Anal. Calcd for C₂₃H₂₈N₄O₄: C, 65.08; H, 6.65; N, 13.20. Found C, 64.74;H, 6.58; N, 12.98. Mp (° C.)=146.

Example 6 Preparation ofN-(3-Dimethylaminopropyl)-4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzamidefrom benzoyl chloride

a) 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

A suspension of 4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.00 g,4.9 mmol) and pyridine (0.391 g, 5.0 mmol) in 7.3 mL toluene stirring atroom temperature was added benzoyl chloride. The resultant heavy whitesuspension was heated at 100□ C. for twenty minutes then at 140 DC fortwenty minutes. After cooling to room temperature the mixture wastreated with EtOAc and H₂O. The suspension was triterated then filteredto afford 0.652 g (48%) of 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoicacid methyl ester. The filtrate phases were separated. The organic phasewas dried over sodium sulfate, filtered, concentrated to afford a solid.The solid was crystallized from acetone: diethyl ether to afford 0.371(27%) of 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester.

¹HNMR (DMSO-d6) δ 8.27 (m, 2H), 8.16 (m, 4H), 7.62–7.71 (m, 3H), 3.91(s, 3H). IR (KBr, cm⁻¹) 1723, 1545, 1447, 1442, 1280, 1118, 1110, 1018,780, 717, 688. MS (ES) m/e, 281. Anal. Calcd for C₁₆H₁₂N₂O₃: C, 68.57;H, 4.32; N, 9.99. Found C, 68.47; H, 4.42; N, 10.03.

b) 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester (0.938 g,3.3 mmol) and lithium hydroxide (0.240 g, 10.0 mmol) to afford 0.889 g(100%) of 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid as a solid.

¹HNMR (DMSO-d6) 813.29 (bs, 1H), 8.21–8.28 (m, 2H), 8.13–8.19 (m, 4H),7.61–7.69 (m, 3H). IR (KBr, cm⁻¹) 3436, 1683, 1547, 1425, 1287, 718,689. MS (ES) m/e, 267, 265. Anal. Calcd for C₁₅H₁₀N₂O₃: C, 67.67; H,3.79; N, 10.52. Found C, 64.26; H, 3.76; N, 9.94.

c) N-(3-Dimethylaminopropyl)-4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzoic acid (0.536 g, 2.0 mmol),1,1′-carbonyldiimidazole (0.3300 g, 2.0 mmol) and3-(dimethylamino)propylamine (0.412 g, 4.0 mmol) and 1.3 mL DMF toafford a solid. Crystallization from methanol:diethyl ether afforded0.286 g (41%) ofN-(3-Dimethylaminopropyl)-4-(5-phenyl-[1,3,4]oxadiazol-2-yl)benzamide.

¹H NMR (DMSO-d6)

8.73 (t, 1H, J=5 Hz), 8.23 (d, 2H, J=7 Hz), 8.15–8.20 (m, 2H), 8.05 (d,2H, J=7 Hz), 7.61–7.69 (m, 3H), 3.31 (m, 2H), 2.27 (t, 2H, J=7 Hz), 3.31(m, 2H), 1.63–1.73 (m, 2H). IR (KBr, cm⁻¹) 3330, 2941, 2763, 1667, 1646,1547, 1492, 715. MS (S) m/e, 351, 349. Anal. Calcd for C₂₀H₂₂N₄O₂: C,68.55; H, 6.33; N, 15.99. Found C, 68.08; H, 6.29; N, 15.90. Mp(°C.)=130.

Example 7 Preparation of4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylaminopropyl)benzamidefrom phenylacetic acid

a) 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from phenyl acetic acid (0.470 g, 3.5mmol), 1,3-dicyclohexylcarbodiimide (0.710 g, 3.5 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.700 g, 3.5 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 25% to 50% EtOAc:hexane)followed by crystallization of the isolated material from diethyl etherafforded 0.421 g (69%) of 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acidmethyl ester.

¹H NMR (DMSO-d6) δ 8.08–8.16 (m, 4H), 7.28–7.41 (m, 5H), 4.39 9s, 2H),3.89 (s, 3H). IR (KBr, cm⁻¹) 1716, 1559, 1551, 1435, 1276, 1111, 779,728, 723, 710. MS (ES) m/e, 295. Anal. Calcd for C₁₇H₁₄N₂O₃: C, 69.38;H, 4.79; N, 9.52. Found C, 69.27; H, 4.78; N, 9.52.

b) 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acid

A mixture of 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester(0.413 g, 1.4 mmol) and lithium hydroxide (0.125 g, 5.2 mmol) in 4.1 mLTHF and 1.8 mL H₂O was stirred at room temperature for fours hours.Next, concentrated HCl (450 uL, 5.2 mmol) was added. The resultantsuspension was reduced in volume then filtered to afford 0.393 g (85%)of 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acid.

¹H NMR (DMSO-d6)

13.33 (bs, 1H), 8.06–8.14 (m, 4H), 7.27–7.42 (m, 5H), 4.39 (s, 2H). IR(KBr, cm⁻¹) 1706, 1685, 1583, 1563, 1552, 1432, 1323, 1290, 872, 716,706. MS (ES) m/e, 281, 279. Anal. Calcd for C₁₆H₁₂N₂O₃: C, 68.57; H,4.32; N, 9.99. Found C, 68.38; H, 4.43; N, 9.99.

c) 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylaminopropyl)benzamide

A suspension of 4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)benzoic acid (0.255 g,0.91 mmol), 1-hydroxybenzotriazole (0.123 g, 0.91 mmol), 4-dimethylaminopyridine (0.011 g, 0.09 mmol) and 1,3-dicyclohexylcarbodiimide (0.206 g,1.00 mmol) in 26 mL CH₂Cl₂ was stirred at room temperature for fifteenminutes. Next, 3-(dimethylamino)propyl amine (0.093 g, 0.91 mmol) wasadded and the reaction was stirred 21 hours at room temperature. Thesuspension was filtered and the filtrate was reduced in volume.Purification by radial chromatography on silica gel (elution with90:10:1 CH₂Cl₂:MeOH:NH₄OH) followed by crystallization of the isolatedmaterial from ethanol:diethyl ether afforded 0.054 g (16%) of4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylaminopropyl)benzamide. Asecond lot of crystals was obtained to afford 0.017 g (5%) of4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylamino-propyl)benzamide.

¹H NMR (DMSO-d6)

8.70 (t, 1H, J=5 Hz), 8.04 (d, 2H, J=9 Hz), 8.00 (d, 2H, J=9 Hz),7.29–7.41 (m, 5H), 4.38 (s, 2H), 3.31 (m, 2H), 2.25 (t, 2H, J=7 Hz),2.13 (s, 6H), 1.61–1.70 (m, 2H). IR (KBr, cm⁻¹) 3298, 2943, 2768, 1937,1636, 1555, 1324, 1087, 863, 721, 706. MS (ES) m/e, 365, 363. Anal.Calcd for C₂₁H₂₄N₄O₂: C, 69.21; H, 6.64; N, 15.37. Found C, 68.91; H,6.71; N, 15.38. Mp(° C.)=110.

Example 8 Preparation ofN-(3-dimethylaminopropyl)-4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzamidefrom hydrocinnamoyl chloride

a) 4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

A solution of 4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.00 g,4.9 mmol) and hydrocinnamoyl chloride (0.826 g, 4.9 mmol) in 10 mLtoluene was heated at 100° C. for five hours. The mixture was thenconcentrated to an oil. The oil was dissolved into CH₂Cl₂ and washedwith 0.1 N HCl. The aqueous phase was extracted with CH₂Cl₂. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated to afford a solid. Purification by HPLC on silica gel(eluted with a linear gradient of 10 to 25% EtOAc:toluene over a thirtyminute period) afforded 0.604 g (40%) of4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester as awhite solid.

¹H NMR (DMSO-d6) δ 8.15 (d, 2H, J=9 Hz), 8.09 (d, 2H, J=9 Hz), 7.18–7.31(m, 5H), 3.90 (s, 3H), 3.28 (t, 2H, J=7 Hz), 3.12 (t, 2H, J=7 Hz). IR(KBr, cm⁻¹) 1714, 1415, 1278, 1111, 774, 713, 696. MS (ES) m/e, 309.Anal. Calcd for C₁₈H₁₆N₂O₃: C, 70.12; H, 5.23; N, 9.09. Found C, 69.55;H, 5.14; N, 9.03.

b) 4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester (0.600 g,2.0 mmol) and lithium hydroxide (0.140 g, 5.8 mmol), to afford 0.510 g(89%) of 4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid.

¹HNMR (DMSO-d6) δ 13.33 (bs, 1H), 8.13 (d, 2H, J=9 Hz), 8.07 (d, 2H, J=9Hz), 7.18–7.33 (m, 5H), 3.28 (t, 2H, J=7 Hz), 3.12 (t, 2H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1670, 1568, 1555, 1420, 1280, 1017. MS (ES) m/e, 295, 293.Anal. Calcd for C₁₇H₁₄N₂O₃: C, 69.38; H, 4.79; N, 9.52. Found C, 68.95;H, 4.57; N, 9.40.

c)N-(3-dimethylaminopropyl)-4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzamide

A suspension of 4-(5-phenethyl-[1,3,4]oxadiazol-2-yl)benzoic acid (0.480g, 1.6 mmol), 1-hydroxybenzotriazole (0.337 g, 2.5 mmol),3-(dimethylamino)propyl amine (0.286 g, 2.8 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.597 g, 3.11 mmol) in 46mL THF was stirred at room temperature for twenty four hours. Theresultant suspension was filtered and the filtrate was concentrated toan oil. The oil was dissolved into EtOAc then washed with 2N sodiumhydroxide (2×25 ml), water then brine. The organic phase was dried oversodium sulfate, filtered, concentrated to afford a white solid.Crystallization of this material from methanol:diethyl ether affored0.354 g (57%) ofN-(3-dimethylaminopropyl)-4-(5-phenethyl)-[1,3,4]oxadiazol-2-yl)benzamide.

¹H NMR (DMSO-d6)

8.70 (t, 1H, J=5 Hz), 8.04 (d, 2H, J=9 Hz), 8.01 (d, 2H, J=9 Hz),7.19–7.30 (m, 5H), 3.26–3.33 (m, 4H), 3.12 (t, 2H, J=8 Hz), 2.26 (t, 2H,J=7 Hz), 2.14 (s, 6H), 1.62–1.71 (m, 2H). IR (CHCl₃, cm⁻¹) 3346, 2973,2942, 2813, 2764, 1636, 1585, 1564, 1552, 1530, 1496, 1496, 1287. MS(ES) m/e, 379, 377. Anal. Calcd for C₂₂H₂₆N₄O₂: C, 69.82; H, 6.92; N,14.80. Found C, 69.62; H, 6.84; N, 14.80. Mp(° C.)=126.

Example 9 Preparation ofN-(3-dimethylaminopropyl)4-(5-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzamidefrom 4phenylbutyric acid

a) 4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 4-phenylbutyric acid (0.470 g,3.5 mmol), 1,3-dicyclohexylcarbodiimide (0.710 g, 3.5 mmol),4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.700 g, 3.4 mmol) and5.1 mL toluene to afford the title compound as a crude material.Purification by radial chromatography on silica gel (elution with 25% to50% EtOAc:hexane) followed by crystallization of the isolated materialfrom diethyl ether afforded 0.554 g (50%) of4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester.

¹H NMR (DMSO-d6), δ 8.14 (d, 2H, J=6 Hz), 8.11 (d, 2H, J=6 Hz),7.15–7.32 (m, 5H), 3.90 (s, 3H), 2.95 (t, 2H, J=7 Hz), 2.72 (t, 2H, J=7Hz), 2.04–2.14 (m, 2H). IR (KBr, cm⁻¹) 1724, 1713, 1587, 1572, 1415,1281, 1275, 1114, 1107, 751, 718. MS (ES) m/e, 323. Anal. Calcd forC₁₉H₁₈N₂O₃: C, 70.79; H, 5.63; N, 8.69. Found C, 70.60; H, 5.65; N,8.71.

b) 4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester(0.512 g, 1.6 mmol) and lithium hydroxide (0.092 g, 3.8 mmol) to afford0.333 g (85%) of 4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzoicacid.

¹H NMR (DMSO-d6)

13.33 (bs, 1H), 8.12 (d, 2H, J=9 Hz), 8.08 (d, 2H, J=$$ 9 Hz), 7.15–7.32(m, 5H), 2.95 (t, 2H, J=7 Hz), 2.72 (t, 2H, J=7 Hz), 2.04–2.14 (m, 2H).IR (KBr, cm⁻¹) 1685, 1565, 1322, 1302, 1287, 722. MS (ES) m/e, 309, 307.Anal. Calcd for C₁₈H₁₆N₂O₃: C, 70.12; H, 5.23; N, 9.09. Found C, 70.05;H, 5.20; N, 9.00.

c)N-(3-dimethylaminopropyl)-4-(5-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from4-[5-(3-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzoic acid (0.430 g, 1.39mmol), 1-hydroxybenzotriazole (0.188 g, 1.39 mmol), 4-dimethylaminopyridine 0.150 g, 1.46 mmol), 3-(dimethylamino)propylamine (0.150 g,1.46 mmol) to afford the title compound as a crude mixture. Purificationby radial chromatography on silica gel (eltuted with 10% 2M ammonium:CH₂Cl₂) followed by crystallization of the isolated material fromethanol:diethyl ether afforded 0.274 g (50%) ofN-(3-dimethylaminopropyl)-4-(5-phenylpropyl)-[1,3,4]oxadiazol-2-yl)benzamide.

¹H NMR (DMSO-d6) δ 8.70 (t, 1H, J=5 Hz), 7.99-8.08 (m, 4H), 7.16–7.33(m, 5H), 3.53 (m, 2H), 3.30 (t, 2H, J=7 Hz), 2.72 (t, 2H, J=7 Hz), 2.27(t, 2H, J=7 Hz), 2.13 (s, 6H), 2.04–2.11 (m, 2H), 1.63–1.72 (m, 2H). IR(CHCl₃, cm⁻¹) 3008, 2950, 2827, 1652, 1586, 1567, 1557, 1529, 1495,1243, 1089. MS (ES) m/e, 393, 391. Anal. Calcd for C₂₃H₂₈N₄O₄: C, 70.38;H, 7.19; N, 14.27. Found C, 69.78; H, 7.04; N, 14.04. Analytical HPLC:100% purity. Mp(° C.)>200.

Example 10 Preparation ofN-(3-dimethylaminopropyl)-4-(5-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzamidefrom 5-phenylvaleric acid

a) 4-[5-(3-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 5-phenylvaleric acid (0.620 g,3.5 mmol), 1,3-dicyclohexylcarbodiimide (0.710 g, 3.5 mmol),4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.700 g, 3.4 mmol) and5.1 mL toluene to afford the title compound as a crude mixture.Purification by radial chromatography on silica gel (elution with 25% to50% EtOAc:hexane) followed by crystallization of the isolated materialfrom diethyl ether afforded 0.463 g (40%) of4-[5-(3-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester.

¹HNMR (DMSO-d6)

8.09–8.17 (m, 4H), 7.14–7.30 (m, 5H), 3.90 (s, 3H), 2.99 (t, 2H, J=7Hz), 2.64 (t, 2H, J=7 Hz), 1.65–1.85 (m, 4H). IR (KBr, cm⁻¹) 1723, 1568,1413, 1277, 1111, 716, 697. MS (ES) m/e, 337. Anal. Calcd forC₂₀H₂₀N₂O₃: C, 71.41; H, 5.99; N, 8.33. Found C, 71.36; H, 5.90; N,8.29.

b) 4-[5-(3-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, using4-[5-(3-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester(0.380 g, 1.16 mmol) and lithium hydroxide (0.081 g, 3.4 mmol) to afford0.360 g (99%) of 4-[5-(3-phenylbutyl)-[1,3,4]oxa-diazol-2-yl)benzoicacid.

¹H NMR (DMSO-d6)

13.38 (bs, 1H),8.04–8.14 (m, 4H), 7.14–7.30 (m, 5H), 2.99 (t, 2H, J=7Hz), 2.64 (t, 2H, J=7 Hz), 1.64–1.85 (m, 4H). IR (KBr, cm⁻¹) 2946, 1686,1586, 1567, 1551, 1429, 1413, 1320, 1288, 740, 716. MS (ES) m/e, 323,321. Anal. Calcd for C₁₉H₁₈N₂O₃: C, 70.79; H, 5.63; N, 8.69. Found C,70.33; H, 5.38; N, 8.41.

c)4[5-(3-dimethylaminopropyl)-4-(5-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from4-[5-(3-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzoic acid (0.342 g, 1.0mmol), 1-hydroxybenzotriazole 0.136 g, 1.0 mmol), 4-dimethylaminopyridine (0.012 g, 0.10 mmol), 3-(dimethylamino)propylamine (0.108 g,1.06 mmol) and 29 mL CH₂Cl₂. Purification by radial chromatography onsilica gel (eluted with 10% 2M ammonium:CH₂Cl₂) followed bycrystallization of the iosolated material from ethanol:diethyl etherafforded 0.226 g (55%) of4[5-(3-dimethylaminopropyl)-4-(5-phenylbutyl)-[1,3,4]oxadiazol-2-yl)benzamide.

¹HNMR (DMSO-d6)

8.71 (t, 1H, J=5 Hz), 7.99–8.06 (m, 4H), 7.14–7.30 (m, 5H), 3.32 (m,2H), 2.98 (t, 2H, J=7 Hz), 2.64 (t, 2H, J=7 Hz), 2.26 (t, 2H, J=7 Hz),2.14 (s, 6H), 1.62–1.82 (m, 6H). IR (CHCl₃, cm⁻¹) 3008, 2947, 1652,1586, 1567, 1556, 1529, 1495. MS (ES) m/e, 407, 405. Anal. Calcd forC₂₄H₃₀N₄O₂: C, 70.91; H, 7.44; N, 13.78. Found C, 70.66; H, 7.35; N,13.67. Mp(° C.)=84.

Example 11 Preparation ofN-(3-dimethylaminopropyl)-4-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzamidefrom 6-phenylhexanoic acid

a) 4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 6-phenylhexanoic acid (0.960 g,5.0 mmol), 1,3-dicyclohexylcarbodiimide (1.01 g, 5.0 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.01 g, 4.95 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 25% to 50% EtOAc:hexane)afforded 0.766 g (44%) of4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester.

¹H NMR (DMSO-d6)

8.10–8.17 (m, 4H), 7.11–7.28 (m, 5H), 3.90 (s, 3), 2.95 (t, 2H, J=7 Hz),2.59 (t, 2H, J=8 Hz), 1.81 (dt, 2H, J=8 Hz), 1.63 (dt, 2H, J=8 Hz),1.35–1.45 (m, 2H). IR (CHCl₃, cm⁻¹) 3010, 2938, 2860, 1721, 1569, 1438,1282, 1119, 1111. MS (ES) m/e, 351. Anal. Calcd for C₂₁H₂₂N₂O₃: C,71.98; H, 6.33; N, 7.99. Found C, 72.04; H, 6.32; N, 8.00.

b) 4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester(0.7.25 g, 2.1 mmol), lithium hydroxide (0.149 g, 6.2 mmol) to afford0.685 g (98%) of 4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoicacid.

¹H NMR (DMSO-d6)

13.33 (bs, 1H), 8.07–8.15 (m, 4H), 7.12–7.28 (m, 5H), 2.95 (t, 2H, J=7Hz), 2.59 (t, 2H, J=7 Hz), 1.74–1.86 (m, 2H), 1.56–1.70 (m, 2H),1.35–1.45 (m, 2H). IR (KBr, cm⁻¹) 2949, 2919, 2856, 1683, 1570, 1321,1291, 732, 720. MS (ES) m/e, 337, 335. Anal. Calcd for C₂₀H₂₀N₂O₃: C,71.41; H, 5.99; N, 8.33. Found C, 70.86; H, 5.96; N, 8.26.

c)4[5-(3-dimethylaminopropyl)-4-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from4-[5-(3-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzoic acid (0.500 g, 1.49mmol), 1-hydroxybenzotriazole (0.201 g, 1.49 mmol), 4-dimethylaminopyridine (0.018 g, 0.15 mmol), and 3-(dimethylamino)propylamine (0.159g, 1.56 mmol) to afford the title compound as a crude mixture.Purification by chromatography on silica gel (eltuted with a lineargradient of 2 to 10% 2M ammonium:CH₂Cl₂ over a thirty minute period)followed by crystallization of the isolated material fromethanol:diethyl ether afforded 0.209 g (33%) of4[5-(3-dimethylaminopropyl)-4-(S-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzamide.A second crop of crystals afforded 0.085 g (13%) of the title compound.

¹H NMR (DMSO-d6)

8.71 (t, 1H, J=5 Hz), 8.00–8.07 (m, 4H), 7.12–7.28 (m, 5H), 3.30 (m,2H), 2.94 (t, 2H, J=7 Hz), 2.59 (t, 2H, J=7 Hz), 2.26 (t, 2H, J=7 Hz),2.14 (s, 6H), 1.76–1.86 (m, 2H), 1.58–1.71 (m, 4H), 1.37–1.45 (m, 2H).IR (CHCl₃, cm⁻¹) 3007, 1652, 1586, 1555, 1529, 1494. MS (ES) m/e, 421,419. Anal. Calcd for C₂₅H₃₂N₄O₂: C, 71.40; H, 7.67; N, 13.32. Found C,71.16; H, 7.64; N, 13.23. Mp(° C.)=116.

Example 12 Preparation ofN-(3-dimethylaminopropyl)-4-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl)benzamidefrom 7-phenylheptanoic acid

a) 4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 7-phenylheptanoic acid (0.714 g,3.46 mmol), 1,3-dicyclohexylcarbodiimide (0.714 g, 3.46 mmol),4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.700 g, 3.43 mmol) and5.1 mL toluene to afford the title compound as a crude mixture.Purification by radial chromatography on silica gel (elution with 25% to50% EtOAc:hexane) afforded 0.738 g (59%) of4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester.

¹H NMR (DMSO-d6)

8.10–8.17 (m, 4H), 7.12–7.28 (m, 5H), 3.90 (s, 3H), 2.94 (t, 2H, J=7Hz), 2.56 (t, 2H, J=7 Hz), 1.72–1.82 (m, 2H), 1.53–1.63 (m, 2H),1.28–1.46 (m, 4H). IR (KBr, cm⁻¹) 2952, 2930, 2856, 1723, 1565, 1414,1280, 1264, 1110, 778, 717, 698. MS (ES) m/e, 365. Anal. Calcd forC₂₂H₂₄N₂O₃: C, 72.51; H, 6.64; N, 7.69. Found C, 72.83; H, 6.59; N,7.62.

b) 4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester(0.676 g, 1.93 mmol) and lithium hydroxide (0.139 g, 5.79 mmol) toafford 0.616 g (95%) of4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid.

¹HNMR (DMSO-d6)

8.05–8.13 (m, 4H), 7.12–7.28 (m, 5H), 2.93 (t, 2H, J=7 Hz), 2.56 (t, 2H,J=8 Hz), 1.72–1.82 (m, 2H), 1.50–1.63 (m, 2H), 1.26–1.46 (m, 4H). IR(KBr, cm⁻¹) 2942, 2924, 2853, 1686, 1573, 1429, 1287, 715. MS (ES) m/e,351, 349. Anal. Calcd for C₂₁H₂₂N₂O₃: C, 71.98; H, 6.33; N, 7.99. FoundC, 71.59; H, 6.45; N, 7.86.

c)4[5-(3-dimethylaminopropyl)-4-(5-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from4-[5-(3-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzoic acid (0.488 g, 1.39mmol), 1-hydroxybenzotriazole (0.188 g, 1.39 mmol), 4-dimethylaminopyridine (0.017 g, 0.14 mmol) and 3-(dimethylamino)propylamine (0.149 g,1.46 mmol) to afford the title compound as a crude mixture. Purificationby radial chromatography on silica gel (eltuted with a 10% 2Mammonium:CH₂Cl₂) followed by crystallization of the isolated materialfrom ethanol:diethyl ether afforded 0.152 g (25%) of4[5-(3-dimethylaminopropyl)-4-(5-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzamide.

¹H NMR (DMSO-d6)

8.71 (t, 1H, J=5 Hz), 8.00–8.08 (m, 4H), 7.12–7.238 (m, 5H), 3.31 (m,2H), 2.93 (t, 2H, J=7 Hz), 2.56 (t, 2H, J=8 Hz), 2.27 (t, 2H, J=7 Hz),2.13 (s, 6H), 1.53–1.79 (m, 6H), 1.30–1.44 (m, 4H). IR (KBr, cm⁻¹) 2936,2861, 1652, 1586, 1567, 1556, 1529, 1495, 1302. MS (ES) m/e, 435, 433.Anal. Calcd for C₂₆H₃₄N₄O₂: C, 71.86; H, 7.89; N, 12.89. Found C, 71.59;H, 7.69; N, 12.72. Mp(° C.)=91.

Example 13 Preparation ofN-(3-dimethylaminopropyl)-4-(5-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzamidefrom 8-phenyloctanoic acid

a) 4-[5-(3-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 8-phenyloctanoic acid (0.763 g,3.46 mmol), 1,3-dicyclohexylcarbodiimide (0.714 g, 3.46 mmol) and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.700 g, 3.43 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 25% to 50% EtOAc:hexane)followed by crystallization of the isolated material from diethyl etherafforded 0.522 g (40%) of4-[5-(3-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester.

¹H NMR (DMSO-d6)

8.13 (m, 4H), 7.12–7.28 (m, 5H), 3.90 (s, 3H), 2.94 (t, 2H, J=7 Hz),2.56 (t, 2H, J=7 Hz), 1.63–1.81 (m, 2H), 1.44–1.61 (m, 21), 1.22–1.41(m, 6H). IR (KBr, cm⁻¹) 2926, 1724, 1570, 1437, 1280, 1110, 712. MS (ES)m/e, 379. Anal. Calcd for C₂₃H₂₆N₂O₃: C, 72.99; H, 6.92; N, 7.40. FoundC, 73.11; H, 7.08; N, 7.68.

b) 4-[5-(3-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzoic acid

Preparation ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 3-phenylpropylmercaptan

a) (3-phenylpropylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1a, from 3-phenylpropylmercaptan (3.13 g,20.6 mmol), sodium hydride (0.823 g, 20.6 mmol), and methyl bromoacetate(2.86 g, 18.7 mmol) to afford the title compound as a crude mixture.Purification by flash filtration chromatography on silica gel (elutionwith 4×250 mL 15% EtOAc:hexane followed by 3×250 mL EtOAc) afforded 3.83g, (89%) of (3-phenylpropylsulfanyl)acetic acid.

¹HNMR (DMSO-d6)

12.51 (bs, 1H), 7.15–7.30 (m, 5H), 3.23 (s, 2H), 2.65 (t, 2H, J=8 Hz),2.58 (t, 2H, J=7 Hz), 1.78–1.88 (m, 2H). IR (CHCl₃, cm⁻¹) 3029, 3011,1710, 1601, 1454, 1423, 1295, 1197. MS (ES) m/e, 209. Anal. Calcd forC₁H₁₄O₂S: C, 62.83; H, 6.71. Found C, 62.70; H, 6.52.

b) 4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from (3-phenylpropylsulfanyl)aceticacid (0.975 g, 4.6 nM), 1,3-dicyclohexylcarbodiimide (0.957 g, 4.6mmol), and 4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.789 g, 3.9mmol) to afford the title compound as a crude mixture.

Purification by radial chromatography on silica gel followed bycrystallization from diethyl ether afforded a total of 0.668 g (47%) of4-[5-(3-phenylpropylsulfanylmethyl) [1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester.

¹H NMR (DMSO-d6)

8.09–8.18 (m, 4H), 7.12–7.26 (m, 5H), 4.14 (s, 2H), 3.91 (s, 3H),2.62–2.67 (m, 4H), 1.80–1.90 (m, 2H). IR (CHCl₃, cm⁻¹) 1721, 1554, 1438,1299, 1283, 1119, 1111. MS (ES) m/e, 369. Anal. Calcd for C₂₀H₂₀N₂O₃S:C, 65.20; H, 5.47; N, 7.60. Found C, 65.05; H, 5.48; N, 7.67.

c) 4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester (0.600 g, 1.63 mmol) and lithium hydroxide (0.117 g, 4.89mmol) to afford 0.522 g (90%) of4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid.

¹H NMR (DMSO-d6)

8.03–8.16 (m, 4H), 7.11–7.28 (m, 5H), 4.14 (s, 2H), 2.66 (dt, 4H, J=7Hz), 1.79–1.88 (m, 2H).

IR (KBr, cm⁻¹) 1706, 1685, 1551, 1433, 1324, 1293, 715, 699.

MS (ES) m/e, 355, 353. Anal. Calcd for Cl₉H₁₈N₂O₃S: C, 64.39; H, 5.12;N, 7.90. Found C, 63.29; H, 4.95; N, 7.81.

d)N-(3-dimethylaminopropyl)-4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from 4-[5-(3-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzoic acid methyl ester (0.467 g, 1.23mmol) and lithium hydroxide (0.089 g, 3.70 mmol), in THF (5.4 mL) andwater (1.0 mL) to afford 0.435 g (97%) of4-[5-(3-phenylheptyl)-[1,3,4]-oxadiazol-2-yl)benzoic acid.

¹H NMR (DMSO-d6)

8.06–8.14 (m, 4H), 7.12–7.28 (m, 5H), 2.94 (t, 2H, J=7 Hz), 2.56 (t, 2H,J=7 Hz), 1.69–1.81 (m, 2H), 1.50–1.61 (m, 2H), 1.23–1.41 (m, 6H). IR(KBr, cm⁻¹) 2928, 2922, 2850, 1688, 1585, 1571, 1434, 1321, 1291, 722.MS (ES) m/e, 365, 363. Anal. Calcd for C₂₂H₂₄N₂O₃: C, 72.51; H, 6.64; N,7.69. Found C, 69.19; H, 6.35; N, 7.47.

c)4[5-(3-dimethylaminopropyl)-4-(5-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from4-[5-(3-phenylheptyl)-[1,3,4]oxadiazol-2-yl)benzoic acid (0.399 g, 1.14mmol), 1-hydroxybenzotriazole (0.154 g, 1.14 mmol), 4-dimethylaminopyridine (0.014 g, 0.11 mmol) and 3-(dimethylamino)propylamine (0.122 g,1.20 mmol) to afford the title compound as a crude mixture. Purificationby silica gel radial chromatography (eltuted with a 10% 2M ammonium:CH₂Cl₂) followed by crystallization of the isolated material fromethanol:diethyl ether afforded 0.103 g (20%) of4[5-(3-dimethylaminopropyl)-4-(5-phenylhexyl)-[1,3,4]oxadiazol-2-yl)benzamide.

¹H NMR (DMSO-d6)

8.71 (t, 1H, J=5 Hz), 8.00–8.08 (m, 4H), 7.12–7.28 (m, 5H), 3.32 (m,2H), 2.93 (t, 2H, J=7 Hz), 2.56 (t, 2H, J=8 Hz), 2.26 (t, 2H, J=7 Hz),2.14 (s, 6H), 1.44–1.77 (m, 6H), 1.27–1.40 (m, 6H). IR (CHCl₃, cm⁻¹)3008, 2934, 2859, 2827, 1652, 1586, 1556, 1495. MS (ES) m/e, 449. Anal.Calcd for C₂₇H₃₆N₄O₂: C, 72.29; H, 8.09; N, 12.49. Found C, 72.21; H,8.05; N, 12.50. Mp(° C.)=108.

Example 14

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid(0.492 g, 1.39 mmol), 1,1′-carbonyldiimidazole (0.236 g, 1.46 mmol) and3-(dimethylamino)propylamine (0.170 g, 1.67 mmol) to afford the titlecompound as a crude mixture. Purification by radial chromatography onsilica gel (elution with 10% 2M ammonia in MeOH:CHCl₃) afforded 0.392 g(64%) ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.72 (t, 1H, J=5 Hz), 8.01–8.07 (m, 4H), 7.12–7.26 (m, 5H), 4.13 (s,2H), 2.62–2.67 (m, 4H), 2.27 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.75–1.86(m, 2H), 1.63–1.72 (m, 2H). IR (KBr, cm⁻¹) 3338, 2939, 2813, 2761, 1638,1581, 1552, 1534, 1496, 1456, 1288, 712. MS (ES) m/e, 439, 437. Anal.Calcd for C₂₄H₃₀N₄O₂S: C, 65.73; H, 6.89; N, 12.77. Found C, 65.82; H,6.94; N, 12.74. Mp(° C.)=112.

Example 15 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

a) 4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

A solution of4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester (0.870 g, 2.4 mmol) in 12 mL CH₂Cl₂ stirring at 0° C. wasadded dropwise and peracetic acid (0.673 g, 2.8 mmol). After 2.1 hoursthe mixture was stirred at room temperature for 20 minutes beforeadditional peracetic acid (0.036 g, 0.47 mmol) was added. Fifty minuteslater additional peracetic acid (0.036 g, 0.47 mmol) was added. Twentyminutes after the second addition, the reaction was quenched with 5 mLsaturated aqueous solution of sodium sulfite. The mixture was dilutedwith water then extracted with CH₂Cl₂. The organic phase was washedtwice with H₂O, once with brine, dried over sodium sulfate, filtered,concentrated to afford a solid. Crystallization form acetone afforded0.660 g (73%) of4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester.

¹H NMR (DMSO-d6)

8.11–8.20 (m, 4H), 7.16–7.32 (m, 5H), 4.73–4.78 (m, 1H), 4.51–4.56 (m,1H), 3.90 (s, 31), 2.88–3.05 (m, 2H), 2.72–2.77 (m, 2H), 1.95–2.05 (m,2H). IR (CHCl₃, cm⁻¹) 1722, 1551, 1438, 1283, 1111. MS (ES) m/e, 385.Anal. Calcd for C₂₀H₂₀N₂O₄S: C, 62.16; H, 5.74; N, 7.25. Found C, 62.11;H, 5.22; N, 7.31.

b) 4-[5-(3-phenylpropane-1-sulfinylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester (0.599 g, 1.56 mmol) and lithium hydroxide (0.112 g,4.67 mmol) to afford 0.457 g (79%) of4-[5-(3-phenylpropane-1-sulfinylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid.

¹HNMR(DMSO-d6)

13.40 (bs, 1H), 8.03–8.17 (m, 4H), 7.16–7.23 (m, 5H), 4.75 (d, 1H, J=14Hz), 4.54 (d, 1H, J=14 Hz), 2.88–3.05 (m, 2H), 2.70–2.80 (m, 2H),1.96–2.09 (m, 2H). IR (KBr, cm⁻¹) 2923, 1706, 1685, 1554, 1434, 1324,1292, 1044, 1012, 873, 716, 697. MS (ES) m/e, 371. Anal. Calcd forC₁₉H₂₀N₂O₄S: C, 61.27; H, 5.41; N, 7.52. Found C, 60.74; H, 4.79; N,7.43.

c)N-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(3-phenylpropane-1-sulfinylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid (0.448 g, 1.20 mmol), 1,1′-carbonyldiimidazole (0.205 g, 1.26 mmol)and 3-(dimethylamino)propylamine (0.147 g, 1.44 mmol) to afford thetitle compound as a crude mixture. Crystallization of the crude materialfrom methanol:diethyl ether afforded 0.284 g (45%) ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfinylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.73 (t, 1H, J=5 Hz), 8.05 (m, 4H), 7.17–7.32 (m, 5H), 4.73 (d, 1H, J=14Hz), 4.52 (d, 1H, J=14 Hz), 3.32 (m, 2H), 2.84–3.03 (m, 2H), 2.62–2.70(m, 2H), 2.27 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.94–2.06 (m, 2H),1.62–1.72 (m, 2H). IR (KBr, cm⁻¹) 3334, 1645, 1585, 1554, 1536, 1304,1047, 859 MS (ES) m/e, 455, 453. Anal. Calcd for C₂₄H₃₀N₄O₃S: C, 63.41;H, 6.65; N, 12.32. Found C, 62.86; H, 6.58; N, 12.14. Analytical HPLC:100% Purity. Mp(° C.)=127.

Example 16 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

a) 4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

A solution of4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester (0.970 g, 2.63 mmol) and m-chloroperoxybenzoic acid (1.82g, 5.8 mmol) in 14 mL CH₂Cl₂ was stirred at room temperature for 4.5hours. The mixture was then quenched with 5 mL saturated aqueoussolution of sodium sulfite. The mixture was diluted with water thenextracted with CH₂Cl₂. The organic phase was washed twice with H₂O, oncewith brine, dried over sodium sulfate, filtered, concentrated to afforda solid. Crystallization form acetone afforded 0.733 g (70%) of4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester.

¹H NMR (DMSO-d6)

8.11–8.20 (m, 4H), 7.18–7.33 (m, 5H), 5.25 (s, 2H), 3.91 (s, 3H), 3.38(t, 2H, J=8 Hz), 2.74 (t, 2H, J=8 Hz), 2.02–2.13 (m, 2H). IR (CHCl₃,cm⁻¹) 1722, 1438, 1333, 1299, 1284, 1112. MS (ES) m/e, 401, 399. Anal.Calcd for C₂₀H₂₀N₂O₅S: C, 59.99; H, 5.03; N, 7.00. Found C, 59.93; H,5.12; N, 6.95.

b) 4-[5-(3-phenylpropane-1-sulfonylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester (0.667 g, 1.67 mmol) and lithium hydroxide (0.120 g,5.00 mmol) to afford 0.559 g (87%) of4-[5-(3-phenylpropane-1-sulfonylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid.

¹H NMR (DMSO-d6)

13.38 (bs, 1H), 8.08–8.18 (m, 4H), 7.18–7.34 (m, 5H), 5.25 (s, 2H), 3.38(t, 2H, J=8 Hz), 2.75 (t, 2H, J=8 Hz), 2.01–2.13 (m, 2H). IR (KBr, cm⁻¹)2995, 2675, 2555, 1706, 1685, 1551, 1433, 1321, 1294, 1137, 1131, 1121,717. MS (ES) m/e, 387. Anal. Calcd for C₁₉H₁₈N₂O₅S: C, 59.06; H, 4.70;N, 7.25. Found C, 58.42; H, 4.69; N, 7.11.

c)N-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(3-phenylpropane-1-sulfonylmethyl)[1,3,4]oxadiazol-2-yl]benzoicacid (0.550 g, 1.42 mmol), 1,1′-carbonyldiimidazole (0.242 g, 1.49 mmol)and 3-(dimethylamino)propylamine (0.175 g, 1.71 mmol) to afford thetitle compound as a crude mixture. Crystallization of the crude materialfrom methanol:diethyl ether afforded 0.378 g (56%) ofN-(3-dimethylaminopropyl)-4-[5-(3-phenylpropane-1-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹HNMR (DMSO-d6)

8.74 (t, 1H, J=5 Hz), 8.05 (m, 4H), 7.18–7.34 (m, 5H), 5.23 (s, 2H),3.28–3.40 (m, 4H), 2.74 (t, 2H, J=8 Hz), 2.27 (t, 2H, J=7 Hz), 2.14 (s,6H), 2.02–2.10 (m, 2H), 1.63–1.72 (m, 2H). IR (KBr, cm⁻¹) 3264, 2941,2763, 1634, 1555, 1320, 1166, 1115, 697. MS (ES) m/e, 469. Anal. Calcdfor C₂₄H₃₀N₄O₄S: C, 61.26; H, 6.43; N, 11.91. Found C, 61.38; H, 6.52;N, 11.94. Mp(° C.)=157.

Example 17 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 2-phenoxypropanol

a) (2-Bromo-1-methylethoxy)benzene

A solution of triphenylphosphine (8.63 g, 32.9 mmol) in 94 mL CH₂Cl₂stirring at room temperature was added dropwise, bromine (5.26 g, 32.9mmol) over a twenty minute period. The resultant suspension was stirredat room temperature for 15 minutes then a solution of 2-phenoxypropanol(5.01 g, 32.9 mmol) and imidazole (2.69 g, 39.5 mmol) in 70 mL CH₂Cl₂was added over a 15 minute period. The mixture was stirred at roomtemperature for 2.5 hours then subjected to filtration. The filtrate wasconcentrated in vacuo to afford an oil. Purification by flash filtrationchromatography on silica gel (elution with 15% EtOAc:hexane) afforded4.80 g (68%) of (2-Bromo-1-methylethoxy)benzene.

¹H NMR (DMSO-d6)

7.32–7.39 (m, 2H), 6.92–6.99 (m, 3H), 4.63–4.72 (m, 1H), 3.69 (ddd, 2H,J=5, 11 and 22 Hz), 1.33 (d, 3H, J=6 Hz). IR (CHCl₃, cm⁻¹) 1600, 1588,1495, 1062. MS (ES) m/e, 214. Anal. Calcd for C₉H₁₁BrO: C, 50.26; H,5.15. Found C, 44.83; H, 4.51.

b) (2-Phenoxypropylsulfanyl)acetic acid methyl ester

A solution of methyl thioglycolate (1.64 g, 15.4 mmol) in 61 mL THFstirring at room temperature was added sodium hydride (0.62 g, 15.4mmol). The mixture was stirred fifteen minutes before a solution of2-bromo-1-methylethoxy)benzene (3.02 g, 14.0 mmol) in 3.0 mL THF wasadded. The mixture was stirred at room temperature for two days. Thereaction mixture was diluted with 100 mL EtOAc then washed three timeswith water, brine, dried over sodium sulfate, filtered, concentrated toafford an oil. Purification by chromatography on silica gel (elutionwith a linear gradient of 10 to 25% Et₂O:hexane) afforded 2.20 g(65%)(2-phenoxypropylsulfanyl)acetic acid methyl ester.

¹H NMR (DMSO-d6)

7.24–7.30 (m, 2H), 6.90–6.94 (m, 3H), 4.60–4.66 (m, 1H), 3.61 (s, 3H),3.45 (d, 2H, J=3 Hz), 2.76 (ddd, 2H, J=6, 14, 38 Hz), 1.30 (d, 3H, J=6Hz). IR (CHCl₃, cm⁻¹) 1735, 1599, 1587, 1495, 1438, 1289, 1173, 1132. MS(ES) m/e, 241. Anal. Calcd for C₁₂H₁₆O₃S: C, 59.97; H, 6.71. Found C,49.24; H, 5.39.

c) (2-Phenoxypropylsulfanyl)acetic acid

A mixture of 2-phenoxypropylsulfanyl)acetic acid methyl ester (1.93 g,8.0 mmol) and lithium hydroxide (0.577 g, 24.1 mmol) was stirred at roomtemperature for 5.5 hours. The reaction mixture was quenched withconcentrated HCl (2.02 mL, 8.0 mmol), diluted with EtOAc and water. Thephases were separated and the aqueous phase extracted once with EtOAc.The combined organic phases were washed with brine, dried over sodiumsulfate, filtered, concentrated to afford 1.22 g (67%) of(2-Phenoxypropylsulfanyl)acetic acid.

¹HNMR (DMSO-d6)

7.24–7.31 (m, 2H), 6.89–6.96 (m, 3H), 4.59–4.69 (m, 1H), 3.28–3.39 (m,2H), 2.76–2.95 (m, 2H), 1.30 (d, 3H, J=6 Hz). IR (CHCl₃, cm⁻¹) 2982,2931, 1711, 1599, 1587, 1495, 1291, 1239, 1173, 1131. MS (ES) m/e, 227,225. Anal. Calcd for C₁₁H₁₄O₃S: C, 58.38; H, 6.24. Found C, 58.80; H,6.00.

d) 4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from (2-phenoxypropylsulfanyl)aceticacid (0.950 g, 4.2 nM), 1,3-dicyclohexylcarbodiimide (0.866 g, 4.2mmol), and 4-(1H-tetrazole-5-yl)benzoic acid methyl ester (0.857 g, 4.2mmol) to afford the title compound as a crude mixture.

Purification three times by radial chromatography on silica gel (elutionwith 50% EtOAc:hexane) afforded 0.631 g (39%) of 4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester as anoil that slowly crystallized out.

¹HNMR (DMSO-d6)

8.07–8.16 (m, 4H), 7.20–7.27 (m, 2H), 6.86–6.94 (m, 3H), 4.62–4.68 (m,1H), 4.16–4.27 (m, 2H), 3.91 (s, 3H), 2.89–2.95 (m, 2H), 1.29 (d, 2H,J=6 Hz).

MS (ES) m/e, 385. Anal. Calcd for C₂₀H₂₀N₂O₄S: C, 62.48; H, 5.24; N,7.29. Found C, 62.25; H, 5.00; N, 6.71.

e) 4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17c, from4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acidmethyl ester (0.611 g, 1.59 mmol) and lithium hydroxide (0.114 g, 4.76mmol) to afford 0.573 g (97%) of4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid.

¹H NMR (DMSO-d6)

13.35 (bs, 1H) 8.04–8.14 (m, 4H), 7.21–7.30 (m, 3H), 6.87–6.94 (m, 3H),4.58–4.71 (m, 2H), 4.16–4.27 (m, 2H), 2.88–3.00 (m, 2H), 1.29 (d, 3H,J=6 Hz). IR (CHCl₃, Cm⁻¹) 1700, 1587, 1495, 1240. MS (ES) m/e, 371, 369.

f) N-(3-dimethylaminopropyl)-4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid(0.541 g, 1.46 mmol), 1,1′-carbonyldiimidazole (0.249 g, 1.53 mmol) and3-(dimethylamino)propylamine (0.157 g, 1.53 mmol) to afford the titlecompound as a crude material. Purification by silica gel radialchromatography (elution with 10% 2M NH₃ in MeOH:CH₂Cl₂) followed bytreatment of the isolated material with oxalic acid in acetone affordedthe oxalate salt of N-(3-dimethylaminopropyl)-4-[5-(2-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.85 (t, 1H, J=6 Hz), 8.04 (s, 4H), 7.18–7.27 (m, 2H), 6.87–6.93 (m,3H), 4.63–4.69 (m, 1H), 4.16–4.27 (m, 2H), 3.32–3.39 (q, 2H, J=6 Hz),3.00–3.10 (m, 2H), 2.87–2.98 (m, 2H), 2.75 (s, 6H), 1.86–1.95 (m, 2H),1.29 (d, 2H, J=6 Hz). IR (CHCl₃, cm⁻¹) 3009, 1778, 1656, 1599, 1586,1495, 1302, 1239, 1012. MS (ES) m/e, 455, 453. Anal. Calcd forC₂₄H₃₀N₄O₃S.C₂H₂O₄: C, 57.34; H, 5.92, N, 10.29. Found C, 56.92; H,5.81; N, 10.22. Mp(° C.)=117.

Example 18 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom 1-phenoxy-2-propanol

a) (2-bromopropoxy)benzene

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17a, from 1-phenoxy-2-propanol (7.01 g,46.1 mmol)(containing approximately 10% 2-phenoxypropanol),triphenylphosphine (12.08 g, 46.1 mmol), bromine (7.36 g, 46.1 mM) andimidazole (3.76 g, 55.3 mmol) to afford 9.23 g (93%) of(2-bromopropoxy)benzene as an oil which is contaminated withapproximately 10% (2-bromo-1-methylethoxy)benzene.

¹H NMR (DMSO-d6)

7.26–7.33 (m, 2H), 6.92–6.98 (m, 3H), 4.47–4.56 (m, 1H), 4.13–4.24 (m,2H), 1.72 (d, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 15600, 1588, 1497, 1244,1035. MS (ES) m/e, 216, 214. Anal. Calcd for C₉H₁₁BrO: C, 50.26; H,5.15. Found C, 41.53; H, 4.64.

b) (1-Methyl-2-phenoxyethylsulfanyl)acetic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from (2-bromopropoxy)benzene (3.90g, 18.1 mmol), methylthioglycolate (2.12 g, 19.9 mmol), and sodiumhydride (0.798 g, 19.9 mmol) to afford 2.30 g (53%) of(1-Methyl-2-phenoxyethylsulfanyl)acetic acid methyl ester as an oil.

¹H NMR (DMSO-d6)

7.25–7.32 (m, 2H), 6.90–6.96 (m, 3H), 4.10 (dd, 1H, J=6, 10 Hz), 3.94(dd, 1H, J=7, 10 Hz), 3.44–3.62 (m, 5H), 3.24–3.31 (m, 1), 1.29 (d, 3H,J=7 Hz). IR (CHCl₃, cm⁻¹) 1735, 1600, 1497, 1289, 1243. MS (ES) m/e,241. Anal. Calcd for C₁₂H₁₆O₃S: C, 59.97; H, 6.71. Found C, 59.61; H,6.63.

c) (1-Methyl-2-phenoxyethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17c, from(1-Methyl-2-phenoxyethylsulfanyl)acetic acid methyl ester (2.01 g, 8.36mmol) and lithium hydroxide (0.601 g, 25.1 mmol) to afford 1.84 g (97%)of (1-Methyl-2-phenoxyethylsulfanyl)acetic acid as an oil.

¹H NMR (DMSO-d6) δ 12.51 (bs, 1H), 7.24–7.32 (m, 2H), 6.90–6.95 (m, 3H),4.11 (dd, 1H, J=5, 10 Hz), 3.93 (dd, 1H, J=7, 10 Hz), 3.23–3.48 (m, 3H),1.33 (d, 3H, J=11 Hz). IR (CHCl₃, cm⁻¹) 3010, 1712, 1600, 1587, 1497,1300, 1291, 1243. MS (ES) m/e, 225. Anal. Calcd for C₁₁H₁₄O₃S: C, 58.38;H, 6.24. Found C, 58.34; H, 6.08.

d)4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from(1-Methyl-2-phenoxyethylsulfanyl)acetic acid (1.44 g, 6.4 nM),1,3-dicyclohexylcarbodiimide (1.31 g, 6.4 mmol), and4-(1H-tetrazole-5-yl)benzoic acid methyl ester (1.30 g, 6.4 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 50% EtOAc:hexane) afforded1.21 g (49%) of4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester as an oil that crystallizes out.

¹H NMR (DMSO-d6) δ 8.07–8.16 (m, 4H), 7.20–7.31 (m, 2H), 6.89–6.96 (m,3H), 4.29 (m, 2H), 4.11–4.15 (m, 1H), 4.00 (dd, 1H, J=7, 10 Hz), 3.91(s, 3H), 3.21–3.33 (m, 1H), 1.33 (d, 3H, J=7 Hz). MS (ES) m/e, 385, 383.Anal. Calcd for C₂₀H₂₀N₂O₄S: C, 62.48; H, 5.24, N, 7.29. Found C, 63.52;H, 5.95; N, 6.91.

e)4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17c, from4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester (1.19 g, 3.1 mmol), and lithium hydroxide (0.222 g,9.3 mmol) to afford 1.06 g (92%) of(4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid as a solid.

¹H NMR (DMSO-d6)

13.36 (bs, 1H), 8.05–8.14 (M, 4 h), 7.20–7.28 (m, 2H), 6.88–6.96 (m,3H), 4.22–4.37 (m, 2H), 4.13 (dd, 1H, J=6, 10 Hz), 4.00 (dd, 1H, J=6, 10Hz), 3.25–3.37 (m, 1H), 1.34 (d, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3010,2934, 2859, 1700, 1600, 1587, 1497, 1286, 1266, 1242. MS (ES) m/e, 371,369.

f)N-(3-dimethylaminopropyl)-4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1d, from4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid (1.04 g, 2.8 mmol), 1,1′-carbonyldiimidazole (0.477 g, 2.9 mmol)and 3-(dimethylamino)propylamine (0.301 g, 2.9 mmol) to afford the titlecompound as a crude mixture. Purification by radial chromatography onsilica gel (elution with 10% 2M NH₃ in MeOH:CH₂Cl₂) followed bycrystallization with EtOH:Et2O afforded 0.404 g (32%) ofN-(3-dimethylaminopropyl)-4-[5-(1-methyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.72 (t, 1H, J=5 Hz), 7.99–8.06 (m, 4H), 7.23–7.28 (m, 2H), 6.89–6.94(m, 3H), 4.22–4.37 (m, 2H), 4.14 (dd, 1H, J=6 and 10 Hz), 4.01 (dd, 1H,J=7 and 10 Hz), 3.27–3.38 (m, 4H), 2.27 (t, 2H, J=7 Hz), 2.14 (s, 6H),1.62–1.72 (m, 2H), 1.33 (d, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 307, 2951,2827, 1652, 1585, 1550, 1496, 1243, 1012. MS (ES) m/e, 455, 453. Anal.Calcd for C₂₄H₃₀N₄O₃S: C, 63.41; H, 6.65, N, 12.32. Found C, 63.57; H,6.62; N, 12.28. Mp(° C.)=84.

Example 19 Preparation of 3-{4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine fromisobutylene sulfide

a) (1,1-dimethyl-2-phenoxyethylsulfanyl)acetic acid methyl ester

A suspension of sodium hydride (0.416 g, 10.4 mmol) (washed twice withhexane) in 30 mL THF stirring at room temperature was added dropwise asolution of phenol (0.978 g, 10.4 mmol) in 3.5 mL THF. The resultantsolution was added to a suspension of chloro(triphenylphosphine)gold(5.14 g, 10.4 mmol) in 30 mL THF over an 80 minute period. Thetemperature of the mixture was maintained between −30° C. and 10° C.(dry ice/CH₃CN) during the addition of the sodium phenolate. Thereaction was then stirred at room temperature for 3.5 hours beforeisobutylene sulfide (0.962 g, 10.9 mmol) was added. The reactioncontinued stirring at room temperature for approximately 4 hours thenmethyl boromacetate (1.75 g, 11.4 mmol) was added. The reaction wasstirred overnight at room temperature. The suspension was treated withCelite, filtered through a pad of Celite and rinsed with diethyl ether.The filtrate was concentrated to an oil which slowly turns into asuspension. The suspension was diluted with hexane, filtered and thefiltrate concentrated to a yellow oil. Purification by chromatography onsilica gel (elution with CH₂Cl₂) afforded 1.66 g (54%) of(1,1-dimethyl-2-phenoxyethylsulfanyl)acetic acid methyl ester a yellowoil.

¹H NMR (DMSO-d6)

7.26–7.31 (m, 2 h), 6.91–6.96 (m, 3H), 3.91 (s, 2H), 3.57 (s, 3H), 3.51(s, 2H), 1.35 (s, 6H).

IR (CHCl₃, cm⁻¹) 3004, 2954, 2932, 2869, 1736, 1600, 1498, 1466, 1290,1245, 1172, 1135. MS (ES) m/e, 255. Anal. Calcd for C₁₃H₁₈O₃S: C, 61.39;H, 7.13. Found C, 61.40; H, 7.17.

b) (1,1-dimethyl-2-phenoxyethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7b, from1,1-dimethyl-2-phenoxyethylsulfanyl)acetic acid methyl ester (1.85 g,7.3 mmol), lithium hydroxide (0.522 g, 21.8 mmol) to afford 1.28 g (73%)of (1,1-dimethyl-2-phenoxyethyl sulfanyl)acetic acid as an oil.

¹HNMR (DMSO-d6)

7.25–7.31 (m, 2H), 6.91–6.95 (m, 3H), 3.92 (s, 2H), 3.40 (s, 2H), 1.35(s, 6H). IR (CHCl₃, cm⁻¹) 2969, 2930, 2871, 1713, 1600, 1587, 1498,1466, 1301, 1291, 1245, 1173. MS (ES) m/e, 240, 239. Anal. Calcd forC₁₂H₁₆O₃S: C, 59.97; H, 6.71. Found C, 43.43; H, 4.94.

c) 4-Hydroxybenzoic acid-N-[2-(1,1-dimethyl-2-phenoxyethylsulfanyl)acetyl]hydrazide

A solution of (1,1-dimethyl-2-phenoxyethylsulfanyl)acetic acid (1.19 g,4.95 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.22 g,4.95 mmol) in 25 mL CH₃CN and 6 mL THF was stirred at room temperaturefor 1 hour. The mixture was then treated with 4-hydroxybenzoic hydrazide(0.753 g, 4.95 mM). The suspension was stirred at room temperature for28 hours. The suspension was filtered, insolubles rinsed with CH₃CN andthe filtrate concentrated to an oil. Purification by chromatography onsilica gel (elution with 50% EtOAc:hexane followed by 75% EtOAc:hexane)afforded 0.910 g (49%) of 4-Hydroxybenzoicacid-N-[2-(1,1-dimethyl-2-phenoxyethylsulfanyl)acetyl]hydrazide as awhite foam.

¹H NMR (DMSO-d6)

9.98–10.15 (m, 2H), 7.75 (d, 2H, J=9 Hz), 7.25–7.31 (m, 2H), 6.91–7.00(m, 3H), 6.81 (d, 2H, J=9 Hz), 3.96 (s, 21), 3.40 (s, 2H), 1.39 (s, 6H).IR(CHCl₃, cm⁻¹) 1685, 1632, 1610, 1600, 1588, 1498, 1467, 1456, 1245,1172. MS (ES) m/e, 375, 373. Anal. Calcd for C₁₉H₂₂N₂O₄S: C, 60.94; H,5.92, N, 7.48. Found C, 60.76; H, 5.91; N, 7.24.

d)4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

A mixture of 4-Hydroxybenzoicacid-N-[2-(1,1-dimethyl-2-phenoxyethylsulfanyl)acetyl]hydrazide (0.860g, 2.3 mmol), triphenylphosphine (1.21 g, 4.6 mmol), triethyl amine(0.837 g, 8.3 mmol) and carbon tetrachloride (1.45 g, 8.3 mmol) in 24 mLCH₃CN was stirred at room temperature for 6.25 hours. The mixture wasthen concentrated to an oil. The oil was dissolved into EtOAc and washedthree times with water and once with brine. The organic phase was driedover sodium sulfate, filtered, concentrated in vacuo to afford an oil.Purification by silica gel chromatography (elution with a lineargradient of 0 to 5% methanol:CHCl₃ over a twenty minute period) afforded4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoland triphenyl phosphine oxide as an oil that slowly crystallizes out.The mixture was duiluted with diethyl ether then filtered. The filtratewas concentrated to an oil. Purification by slicia gel radialchromatography (elution with 50% Et₂O:hexane) followed bycrystallization from MeOH:Et₂O afforded 0.499 g (61%) of4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.30 (bs, 11H), 7.76 (m, 2H), 7.73 (m, 2H), 7.21–7.28 (m, 2H),6.90–6.94 (m, 3H), 4.23 (s, 2H), 3.96 (s, 2H), 1.40 (s, 6H). IR (KBr,cm⁻¹) 3158, 1610, 1598, 1588, 1499, 1467, 1286, 1244, 1173, 757. MS (ES)m/e, 357, 355. Anal. Calcd for C₁₉H₂₀N₂O₃S: C, 64.02; H, 5.66; N, 7.86.Found C, 63.91; H, 5.65; N, 7.77.

e)3-{4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

To a solution of4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.205 g, 1.3 mmol) in 16.4 mL DMF stirring at room temperature wasadded sodium hydride (0.109 g, 2.7 mmol). The mixture was stirred 5minutes then 3-chloro-N,N-dimethylpropyl amine hydrochloride (0.205 g,1.3 mmol) was added. The reaction was heated at 100° C. for 1.45 hours.After cooling to room temperature, the mixture was diluted with 50%EtOAc:hexane and 50% brine:H₂O. The phases were separated and theaqueous phase was extracted with 50% EtOAc:hexane. The combined organicphases were washed with 50% brine:H₂O the brine. The organic phase wasdried over sodium sulfate, filtered, concentrated to afford 0.533 g anoil. The oil was dissolved into diethyl ether. To this solution wasadded dropwise a solution of EtOH in Et₂O that was treated with 0.103 mLacetyl chloride. The resultant precipitate was collected by filtrationto afford 0.154 g (27%) of3-{4-[5–1,1-dimethyl-2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.86–7.88 (m, 2H), 7.210–7.28 (m, 2H), 7.10–7.15 (m, 2H), 6.90–6.94 (m,3H), 4.25 (s, 2H), 4.16 (t, 2H, J=6 Hz), 3.96 (s, 2H), 3.19–3.24 (m,2H), 2.79 (s, 6H), 2.13–2.22 (m, 2H), 1.40 (s, 6H). IR (CHCl₃, cm⁻¹)2970, 1615, 1500, 1245, 1224, 1175. MS (ES) m/e, 442. Anal. Calcd forC₂₄H₃₁N₃O₃S.HCl: C, 60.30; H, 6.75; N, 8.79. Found C, 59.96; H, 6.59; N,8.64. Mp(° C.)=134.

Example 20 Preparation of1-{5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}-4-phenoxybutan-2-olfrom 3-Oxo-5-phenoxypentanoic acid ethyl ester

a) 3-hydroxy-5-phenoxypentanoic acid ethyl ester

A solution of 3-Oxo-5-phenoxypentanoic acid ethyl ester 910.23 g, 43.3mmol) in 122 mL EtOH and sodium borohydride (0.573 g, 15.2 mmol) wasstirred at room temperature for 2.0 hours. The mixture was then treatedwith H₂O and reduced in volume.

EtOAc and 1N HCl were added, phases separated and the organic phase waswashed with brine, dried over sodium sulfate, filtered, concentrated toafford an oil. Purification by HPLC on silica gel (elution with a lineargradient of 20 to 35% EtOAc:hexane over a 30 minute period) afforded6.55 g (63%) of 3-hydroxy-5-phenoxypentanoic acid ethyl ester as an oil.

¹H NMR (DMSO-d6)

7.24–7.31 (m, 2H), 6.88–6.93 (m, 3H), 4.90 (d, 1H, J=6 Hz), 3.94–4.11(m, 5H), 2.50 (dd, 1H, J=5 and 15 Hz), 2.37 (dd, 1H, J=8 and 15 Hz),1.71–1.88 (m, 2H), 1.18 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3554, 3003,2983, 2932, 1718, 1600, 1498, 1470, 1301, 1245, 1173. MS (ES) m/e, 239.Anal. Calcd for Cl₃H₁₈O₄: C, 65.53; H, 7.61. Found C, 65.32; H, 7.42.

b) 3-hydroxy-5-phenoxypentanoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 8b, from 3-hydroxy-5-phenoxypentanoicacid ethyl ester (6.35 g, 26.6 mmol) and lithium hydroxide 1.91 g, 79.9mmol) to afford 5.08 g (91%) of 3-hydroxy-5-phenoxypentanoic acid as awhite solid.

¹H NMR (DMSO-d6)

7.24–7.31 (m, 2H), 6.88–6.94 (m, 3H), 3.94–4.09 (m, 3H), 2.41 (dd, 1H,J=5, 15 Hz), 2.30 (dd, 1H, J=8, 15 Hz), 1.65–1.93 (m, 2H). IR (CHCl₃,cm⁻¹) 3516, 3028, 2952, 2932, 2883, 1710, 1600, 1498, 1423, 1244, 1230,1173. MS (ES) m/e, 211, 209. Anal. Calcd for C₁₁H₁₄O₄: C, 62.85; H,6.71. Found C, 63.03; H, 6.59.

c) 4-Hydroxybenzoic acid-N-(3-hydroxy-5-phenoxypentanoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 3-hydroxy-5-phenoxypentanoicacid (2.35 g, 8.0 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(1.97 g, 8.0 mmol) and 4-hydroxybenzoic hydrazide (1.21 g, 8.0 mmol) toafford 2.33 g (85%) of 4-Hydroxybenzoic acid-N-(3-hydroxy-5-phenoxypentanoyl)hydrazide as a solid.

¹H NMR (DMSO-d6)

10.07 (bs, 2H), 9.77 (bs, 1H), 7.74 (d, 2H, J=9 Hz), 7.22–7.31 (m, 2H),6.89–6.95 (m, 3H), 6.89–6.95 (m, 3H), 6.80 (d, 2H, J=9 Hz), 4.84 (d, 1H,J=5 Hz), 4.01–4.16 (m, 3H), 2.29–2.43 (m, 2H), 1.89–2.02 (m, 1H),1.68–1.82 (m, 1H). IR (KBr, cm⁻¹) 3413, 3207, 2949, 2875, 1661, 1601,1579, 1475, 1469, 1244, 1056, 835. MS (ES) m/e, 345, 343. Anal. Calcdfor C₁₈H₂₀N₂O₅: C, 62.78; H, 5.85, N, 8.13. Found C, 62.68; H. 5.83; N,8.26.

d) 4-[5-(2-Hydroxy-4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenol

To a heavy suspension of 4-Hydroxybenzoicacid-N-(3-hydroxy-5-phenoxypentanoyl)hydrazide (0.900 g, 2.6 mmol) in 6mL chlorobenzene stirring at room temperature was added1,1,3,3-hexamethyldisilazane (1.31 g, 8.1 mmol) followed bytrifluoromethane sulfonic acid (0.392 g, 2.6 mmol). The mixture was thenheated at 120° C. for 6 hours. After cooling to room temperature thesuspension was filtered. The filtrate was treated with methanol thenconcentrated to an oil. The oil was dissolved into EtOAc and washedtwice with 5N HCl. The aqueous phases were combined then extracted twicewith EtOAc. The organic phases were combined, dried over sodium sulfate,filtered and concentrated to afford an oil. Purification bychromatography on silica gel (elution with 50% EtOAc:hexane) afforded0.280 g (33%) of4-[5-(2-Hydroxy-4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenol as a solid.

¹H NMR (DMSO-d6)

10.24 (bs, 1H), 7.78–7.82 (m, 2H), 7.24–7.31 (m, 2H), 6.89–6.96 (m, 5H),5.14 (d, 1H, J=6 Hz), 4.02–4.21 (m, 3H), 3.11 (dd, 1H, J=5, 15 Hz), 2.99(dd, 1H, J=8, 15 Hz), 1.74–2.05 (m, 2H). IR (CHCl₃, cm⁻¹) 3204, 1617,1599, 1587, 1501, 1473, 1279, 1244, 1173, 844, 754, 739. MS (ES) m/e,327. Anal. Calcd for C₁₈H₁₈N₂O₄: C, 66.25; H, 5.56; N, 8.58. Found C,60.90; H, 4.97; N, 6.95.

e)1-{5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}-4-phenoxybutan-2-ol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-[5-(2-Hydroxy-4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenol (0.260 g0.8 mmol), sodium hydride (0.064 g, 1.6 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.126 g, 0.8 mmol) toafford the title compound as a crude mixture. Purification bychromatography on silica gel (elution with 10% 2M NH₃ in MeOH:Et₂O)followed by crystallization from MeOH:Et2O afforded 0.129 g (39%) of1-{5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}-4-phenoxybutan-2-ol.

¹H NMR (DMSO-d6)

7.88–7.91 (m, 2H), 7.24–7.30 (m, 2H), 7.12 (d, 2H, J=9 Hz), 6.89–6.95(m, 3H), 5.15 (d, 1H, J=6 Hz), 4.07–4.21 (m, 5H), 3.12 (dd, 1H, J=5, 15Hz), 3.00 (dd, 1H, J=8, 15 Hz), 2.35 (t, 2H, J=7 Hz), 2.14 (s, 6H),1.77–2.05 (m, 4H). IR (CHCl₃, cm⁻¹) 3535, 3019, 2953, 2825, 2777, 1614,1500, 1470, 1255, 1174. MS (ES) m/e, 412. Anal. Calcd for C₂₃H₂₉N₃O₄: C,67.13; H, 7.10, N, 10.21. Found C, 66.98; H, 6.96; N, 10.19. Mp(°C.)=93.

Example 21 Preparation ofDimethyl-(3-{4-[5-(5-phenoxypent-1-enyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)aminefrom 4-Phenoxybutan-1-01

a) 6-Phenoxyhex-2-enoic acid ethyl ester

To a solution of oxalyl chloride (5.39 g, 42.5 mmol) in 500 mL CH₂Cl₂ at−78° C. was added dimethyl sulfoxide (6.64 g, 85.0 mmol). The reactionwas stirred 10 minutes before a solution of 4-Phenoxybutan-1-01 (6.42 g,38.6 mmol) in 40 mL CH₂Cl₂ was added dropwise over a 25 minute period.The reaction was continued stirring at −78° C. for 30 minutes beforetriethylamine (19.54 g, 193.1 mmol) was added. The cooling bath wasremoved allowing the reaction to gradually warm to room temperature.Upon warming, at approximately −40° C.(carboethoxymethylene)triphenylphosphorane was added directly followedby 250 mL CH₂Cl₂. The resultant solution was stirred approximately 18hours at room temperature before being concentrated to an oil. Treatmentof the oil with diethyl ether followed by sonication resulted in crystalformation. Crystals were collected by filtration and discarded. Thefiltrate was concentrated to an oil and the above process was repeatedto remove additional triphenylphosphine oxide. Purification bychromatography on silica gel (elution with 10% Et₂O:hexane) afforded7.05 g (78%) of trans-6-Phenoxyhex-2-enoic acid ethyl ester and 0.520 g(6%) of cis-6-Phenoxyhex-2-enoic acid ethyl ester as oils.

¹H NMR (DMSO-d6)

7.24–7.31 (m, 2H), 6.89–7.00 (m, 4H), 5.88 (dt, 1H, J=1 and 15 Hz), 4.10(q, 2H, J=7 Hz), 3.96 (t, 2H, J=6 Hz), 2.36 (ddd, 2H, J=1, 7 and 16 Hz),1.82–1.92 (m, 2H), 1.20 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1711, 1600,1498, 1277, 1246, 1172, 1041. MS (ES) m/e, 235. Anal. Calcd forC₁₄H₁₈O₃: C, 71.77; H, 7.74. Found C, 71.30; H, 7.73.

b) trans-6-Phenoxyhex-2-enoic acid

A solution of trans-6-Phenoxyhex-2-enoic acid ethyl ester (2.25 g, 9.6mmol) in 48 mL acetone and 48 mL 1N lithium hydroxide was stirred atroom temperature for 2.5 hours. The mixture was then quenched with 4.14mL concentrated HCl, reduced in volume and set aside at 5° C. to allowfor crystal formation. Collection of the crystals by filtration afforded1.43 g (72%) of trans-6-phenoxyhex-2-enoic acid.

¹H NMR (DMSO-d6)

12.10 (bs, 1H), 7.24–7.31 (m, 2H), 6.83–6.93 (m, 4H), 5.77–5.83 (m, 1H),3.96 (t, 2H, J=6 Hz), 2.30–2.38 (m, 2H), 1.81–1.91 (m, 2H). IR (KBr,cm⁻¹) 3441, 2942, 1693, 1642, 1291, 1252, 1242, 758. MS (ES) m/e, 205.Anal. Calcd for C₁₂H₁₄O₃: C, 69.89; H, 6.84. Found C, 70.02; H, 7.06.

c) 4-Hydroxybenzoic acid-N-(6-phenoxyhex-2-enoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from trans-6-phenoxyhex-2-enoic acid(1.30 g, 6.3 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.56g, 6.3 mmol) and 4-hydroxybenzoic hydrazide (0.959 g, 6.3 mmol) toafford the title compound as a crude mixture. Purification bycrystallization (MeOH:Et₂O) afforded 1.05 g (49%) of 4-Hydroxybenzoicacid-N-(6-phenoxyhex-2-enoyl)hydrazide.

¹H NMR (DMSO-d6)

10.09 (bs, 2H), 9.87 (bs, 1H), 7.74 (d, 2H, J=9 Hz), 7.22–7.32 (m, 2H),6.89–6.95 (m, 3H), 6.76–6.86 (m, 3H), 6.02–6.07 (m, 1H), 3.99 (t, 2H,J=6 Hz), 2.35 (q, 2H, J=7 Hz), 1.88 (m, 2H). IR (KBr, cm⁻¹) 3284, 3210,3007, 1693, 1618, 1610, 1600, 1585, 1518, 1492, 1291, 1245, 1173, 937,758. MS (ES) m/e, 341, 339. Anal. Calcd for C₁₉H₂₀N₂O₄: C, 67.05; H,5.92; N, 8.23. Found C, 66.90; H, 6.03; N, 8.57.

d) 4-[5-(5-phenoxypent-1-enyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-Hydroxybenzoicacid-N-(6-phenoxyhex-2-enoyl)hydrazide (0.915 g, 2.7 mmol),triphenylphosphine (1.41 g, 5.4 mmol), triethyl amine (0.544 g, 5.4mmol) and carbon tetrabromide (1.78 g, 5.4 mmol) to afford the titlecompound as a crude mixture. Crystallization of this material from EtOAcafforded 0.224 g (26%) of4-[5-(5-phenoxypent-1-enyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.31 (bs, 1H), 7.84–7.89 (m, 2H), 7.25–7.31 (m, 2H), 6.89–6.99 (m, 6H),6.54–6.59 (m, 1H), 4.03 (t, 2H, J=6 Hz), 2.45–2.50 (m, 2H), 1.91–2.00(m, 2H). IR (KBr, cm⁻¹) 2945, 2612, 1656, 1588, 1441, 1288, 1243, 1173,1034, 845. MS (ES) m/e, 323, 321. Anal. Calcd for C₁₉H₁₈N₂O₃: C, 70.79;H, 5.63; N, 8.64. Found C, 70.70; H, 5.78; N, 8.64.

e)Dimethyl-(3-{4-[5-(5-phenoxypent-1-enyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)aminefrom 4-Phenoxybutan-1-01

A suspension of 4-[5-(5-phenoxypent-1-enyl)-[1,3,4]oxadiazol-2-yl]phenol(0.207 g 0.6 mmol), cesium carbonate (0.418 g, 1.3 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.102 g, 0.6 mmol) in8.5 mL DMF was heated at 90° C. for 3.5 hours. After cooling to roomtemperature the reaction was diluted with water then extracted threetimes with EtOAc. The organic phases were combined, washed with brinethen concentrated an oil. Purification by radial chromatography onsilica gel (elution with 10% 2M NH3 in MeOH:CHCl₃) afforded 0.153 g ofthe title compound as an oil. Treatment of the oil, dissolved inacetone, with oxalic acid afforded 0.147 g (46%) of the oxalate salt ofdimethyl-(3-{4-[5-(5-phenoxypent-1-enyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6)

7.97 (d, 2H, J=9 Hz), 7.23–7.31 (m, 2H), 7.15 (d, 2H, J=9 Hz), 6.90–7.03(m, 4H), 6.56–6.62 (m, 1H), 4.15 (t, 2H, J=6 Hz), 4.01–4.05 (m, 2H),2.76 (s, 6H), 2.04–2.17 (m, 2H), 1.87–1.99 (m, 2H). IR (CHCl₃, cm⁻¹)1776, 1658, 1609, 1493, 1471, 1255, 1172. MS (ES) m/e, 408. Anal. Calcdfor C₂₄H₂₉N₃O₃.C₂H₂O₄: C, 62.77; H, 6.28, N, 8.45. Found C, 62.47; H,6.26; N, 8.32. Mp(° C.)=163.

Example 22 Preparation ofDimethyl(3-{4-[5-(5-phenoxypent-2-enyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom Hex-3-enedioic acid monomethyl ester

a) 6-Hydroxyhex-3-enoic acid methyl ester

To a solution of hex-3-enedioic acid monomethyl ester (8.49 g, 53.7mmol) in 23 mL THF at −10° C. was added a 1.0 M solution of borane inTHF over a 140 minute period. The resultant suspension was stirred atroom temperature approximately 24 hours. Next, the mixture was treatedwith 1:1 Acetic acid:H₂O then concentrated to an oil. The oil was addeddropwise to a 100 mL saturated solution of sodium bicarbonate. Thismixture was extracted with EtOAc. The organic phase was washed twicewith the saturated solution of sodium bicarbonate. The combined aqueousphases were acidified with 5N HCl then extracted three times with EtOAc.The combined organic phases were washed with brine, dried over sodiumsulfate, filtered, concentrated in vacuo to afford 4.09 g (53%) of6-Hydroxyhex-3-enoic acid methyl ester as an oil.

¹H NMR (DMSO-d6)

5.45–5.60 (m, 2H), 4.47 (t, 1H, J=5 Hz), 3.59 (s, 3H), 3.40 (ddd, 2H,J=5, 7, 12 Hz), 3.04 (d, 2H, J=6 Hz), 2.14 (q, 2H, J=6 Hz). IR (CHCl₃,cm⁻¹) 3620, 3465, 3023, 2955, 2884, 1733, 1438, 1169, 1044, 971. MS (ES)m/e, 126. Anal. Calcd for C₇H₁₂O₃: C, 58.32; H, 8.39. Found C, 57.43; H,7.99.

b) 6-Phenxoyhex-3-enoic acid methyl ester

To a solution of 6-hydroxyhex-3-enoic acid methyl (1.30 g, 9.0 mmol) andphenol (1.27 g, 13.5) in 81 mL THF stirring at room temperature wasadded, in portions, 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxidetriphenylphosphine adduct (reference: Castro, J. L., Matassa, V. G., J.Org. Chem. 1994, 59, 2289–2291) over a twenty minute period. Afterstirring approximately 24 hours, the reaction was diluted with EtOActhen washed three times with 1N sodium hydroxide, brine, dried oversodium sulfate, filtered, concentrated to a solid. Purification bychromatography on silica gel (elution with 10% Et₂O:hexane) afforded0.987 g (50%) of 6-phenxoyhex-3-enoic acid methyl ester as an oil.

¹H NMR (DMSO-d6)

7.24–7.31 (m, 2H), 6.89–6.94 (m, 3H), 5.62–5.65 (m, 2H), 3.97 (t, 2H,J=7 Hz), 3.60 (s, 3H), 3.09 (m, 2H), 2.42–2.49 (m, 2H). IR (KBr, cm⁻¹)3013, 2954, 1734, 1601, 1497, 1438, 1290, 1245, 1173, 1037, 970. MS (ES)m/e, 220. Anal. Calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32. Found C, 56.90;H, 5.84.

c) 6-Phenxoyhex-3-enoic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17c, from 6-phenxoyhex-3-enoic acidmethyl ester (0.960 g, 4.4 mmol) and lithium hydroxide (0.313 g, 13.1mmol) to afford 0.760 g (85%) of 6-phenxoyhex-3-enoic acid as an oilthat slowly crystallized out upon standing.

¹H NMR (DMSO-d6)

12.29 (bs, 1H), 7.20–7.32 (m, 2H), 6.88–6.96 (m, 3H), 5.54–5.66 (m, 2H),3.97 (t, 2H, J=7 Hz), 2.99 (m, 2H), 2.43–2.48 (m, 2H). IR (KBr, cm⁻¹)1713, 1601, 1471, 1398, 1246, 1225, 1039, 968, 758, 694. MS (ES) m/e,205. Anal. Calcd for C₁₂H₁₄O₃: C, 69.89; H, 6.84. Found C, 69.30; H,6.64.

d) 4-(3-Dimethylaminopropoxy)benzoicacid-N-(6-phenoxyhex-3-enoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 6-phenxoyhex-3-enoic acid(0.760 g, 3.7 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(0.911 g, 3.7 mmol) and 4-(3-dimethylaminopropoxy)benzoic hydrazide(0.874 g, 3.7 mmol) to afford the title compound as an oil. Treatment ofthe oil with EtOAc followed by 1N HCl resulted in crystal formation inthe aqueous phase. The crystals were collected by filtration to afford0.364 g (23%) of 4-(3-Dimethyl aminopropoxy)benzoicacid-N-(6-phenoxyhex-3-enoyl)hydrazide.

¹H NMR (DMSO-d6)

10.17 (s, 1H), 9.86 (s, 1H), 7.85 (d, 2H, J=9 Hz), 7.24–7.31 (m, 2H),7.03 (d, 2H, J=9 Hz), 6.90–6.95 (m, 3H), 5.57–5.69 (m, 2H), 4.13 (t, 2H,J=6 Hz), 3.99 (t, 2H, J=7 Hz), 3.17–3.23 (m, 2H); 2.96 (d, 2H, J=3 Hz),2.44–2.48 (m, 2H), 2.11–2.20 (m, 2H). IR (KBr, cm⁻¹) 3201, 3010, 2591,2563, 2519, 2468, 1683, 1666, 1642, 1609, 1493, 1477, 1467, 1307, 1263,1166, 978, 762. MS (ES) m/e, 426, 424. Anal. Calcd for C₂₄H₃₁N₃O₄: C,62.40; H, 6.98; N, 9.10. Found C, 61.74; H, 6.83; N, 8.72.

e)Dimethyl(3-{4-[5-(5-phenoxypent-2-enyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-Dimethylaminopropoxy)benzoic acid-N-(6-phenoxyhex-3-enoyl)hydrazide(0.348 g, 0.8 mmol), triphenylphosphine (0.217 g, 0.8 mmol), triethylamine (0.160 g, 1.6 mmol) and carbon tetrabromide (0.275 g, 0.8 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (10% 2M NH₃ in MeOH:CHCl₃) afforded 0.224 gof material. The material was dissolved into diethyl ether. To thissolution was added dropwise a solution of EtOH in Et2O that was treatedwith 0.047 mL acetyl chloride. The resultant precipitate was collectedby filtration to afford 0.176 g (53%) ofdimethyl(3-{4-[5-(5-phenoxypent-2-enyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}propyl)amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.87–7.93 (m, 2H), 7.23–7.29 (m, 2H), 7.11–7.16 (m, 2H), 6.89–6.94 (m,3H), 5.78–5.82 (m, 2H), 4.16 (t, 2H, J=6 Hz), 4.01 (t, 2H, J=7 Hz), 3.71(d, 2H, J=5 Hz), 3.18–3.24 (m, 2H), 2.78 (s, 6H), 2.47–2.53 (m, 2H),2.13–2.22 (m, 2H). IR (KBr, cm⁻¹) 2936, 2675, 2658, 2614, 2477, 1617,1501, 1473, 1257, 1175, 972, 839, 769. MS (ES) m/e, 408. Anal. Calcd forC₂₄H₂₉N₃O₃.HCl: C, 64.93; H, 6.81, N, 9.46. Found C, 63.76; H, 6.75; N,9.24. Analytical HPLC: 100% Purity. Mp(° C.)=145.

Example 23 Preparation ofDimethyl-[3(4-{5-[2-(2-phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenoxy)propyl]aminefrom 4-phenoxybutene

a) 2-(2-Phenoxyethyl)cyclopropanecarboxylic acid methyl ester

To a light suspension of 4-phenoxybutene (4.95 g, 33.4 mmol) and rhodiumacetate (0.147 g, 0.33 mmol) in 295 mL CH₂Cl₂ stirring at roomtemperature was added a solution of ethyl diazo acetate (3.81 g, 33.4mmol) in 48 mL CH₂Cl₂ over a four hour period. Stirring continued for anadditional 30 minutes before the mixture was washed twice with 1N HCl,brine, dried over sodium sulfate, filtered, concentrated to afford anoil. Purification by chromatography on silica gel (elution with CH₂Cl₂)afforded 1.29 g (16%) of 2-(2-phenoxyethyl)cyclopropanecarboxylic acidmethyl ester.

¹H NMR (CDCl₃)

7.28 (m, 2H), 6.90–6.94 (m, 3H), 4.12 (m, 2H), 4.02 (ddd, 2H, J=7, 9, 13Hz), 1.82 (ddd, 1H, J=7, 14, 21 Hz), 1.76 (ddd, 1H, J=6, 13, 21 Hz),1.55 (m; 1H), 1.48 (dd, 1H, J=5, 8 Hz), 1.26 (t, 3H), 1.22 (ddd, 1H, 4,4, 9 Hz), 0.79 (ddd, 1H, J=4, 6, 8 Hz). IR (CHCl₃, cm⁻¹) 3009, 2984,2941, 2873, 1717, 1600, 1498, 1302, 1246, 1182, 1039. MS (EI) m/e, 234.Anal. Calcd for C₁₄H₁₈O₃: C, 71.77; H, 7.74. Found C, 69.01; H, 7.53.

b) 2-(2-Phenoxyethyl)cyclopropanecarboxylic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from2-(2-Phenoxyethyl)cyclopropanecarboxylic acid methyl ester (1.07 g, 4.5mmol) and lithium hydroxide (0.33 g, 13.6 mmol) to afford the titlecompound as a crude mixture. The material was treated with water thenextracted twice with EtOAc. The organic phases were combined, dried oversodium sulfate, filtered, concentrated to afford 0.771 g (82%)2-(2-Phenoxyethyl)cyclopropanecarboxylic acid as a solid.

¹H NMR (DMSO-d6)

12.13 (bs, 1H), 7.24–7.31 (m, 2H), 6.89–6.95 (m, 3H), 3.94–4.06 (m, 2H),1.66–1.75 (q, 2H, J=7 Hz), 1.31–1.45 (m, 2H), 1.00 (ddd, 1H, J=4, 8, 17Hz), 0.78 (ddd, 1H, J=4, 6, 8 Hz). IR (CHCl₃, cm⁻¹) 3020, 2943, 1696,1600, 1498, 1246. MS (ES) m/e, 205. Anal. Calcd for Cl₂H₁₄O₃: C, 69.89;H, 6.84. Found C, 69.50; H, 6.90.

c) 4-Hydroxybenzoic acid-N-[2-(2-phenoxyethyl)cyclopropanecarbonyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from2-(2-Phenoxyethyl)cyclopropanecarboxylic acid (0.750 g, 3.6 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.899 g, 3.6 mmol) and4-hydroxybenzoic hydrazide (0.553 g, 3.6 mmol) to afford the titlecompound as a crude mixture. Purification by radial chromatography onsilica gel (elution with 10% MeOH:CHCl₃) followed by crystallizationfrom MeOH:EtOAc afforded 0.336 g (27%) of 4-hydroxybenzoicacid-N-[2-(2-phenoxyethyl)-cyclopropanecarbonyl]hydrazide.

¹H NMR (DMSO-d6) δ 10.06–9.97 (M, 3H), 7.80–7.71 (m, 2H), 7.32–7.21 (m,2H), 6.90–6.96 (m, 3H), 6.79–6.83 (m, 2H),4.02 (t, 2H, J=6 Hz),1.68–1.79 (m, 2H), 1.55–1.61 (m, 1H), 1.28–1.36 (m, 1H), 0.92–0.98 (m,1H), 0.74–0.80 (m, 1H). IR (KBr, cm⁻¹) 3301, 3226, 1696, 1620, 1610,1584, 1518, 1498, 1290, 1248, 1173, 756. MS (ES) m/e, 341, 339. Anal.Calcd for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N, 8.23. Found C, 66.78; H,5.76; N, 8.26.

d) 4-{5-[2-(2-Phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N-[2-(2-phenoxyethyl)cyclopropanecarbonyl]hydrazide (0.308 g, 0.9mmol), triphenylphosphine (0.285 g, 1.1 mmol), triethyl amine (0.110 g,1.1 mmol) and carbon tetrabromide (0.360 g, 1.1 mmol) to afford thetitle compound as a crude mixture. Purification by radial chromatographyon silica gel (elution with EtOAc) afforded 0.247 mg (85%) of(4-{5-[2-(2-Phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenol 0.247g (85%) as a white foam.

¹H NMR (DMSO-d6)

10.23 (bs, 1H), 7.73–7.81 (m, 2H), 7.24–7.31 (m, 2H), 6.88–6.96 (m, 5H,4.05–4.12 (m, 2H), 2.16–2.22 (m, 1H), 1.77–1.90 (m, 2H), 1.56–1.64 (m,1H), 1.26–1.32 (m, 1H), 1.06–1.14 (m, 1H). IR (KBr, cm⁻¹) 3422, 3092,3027, 2954, 2813, 2684, 2606, 1615, 1601, 1585, 1565, 1500, 1478, 1381,1287, 1269, 1249, 1175, 1167, 1078, 1032, 1008, 835, 752, 741, 689. MS(ES) m/e, 323, 321. Anal. Calcd for C₁₉H₁₈N₂O₃: C, 70.79; H, 5.63; N,8.69. Found C, 69.53; H, 5.51; N, 8.28.

e)Dimethyl-[3(4-{5-[2-(2-phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenxoy)propyl]amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-{5-[2-(2-Phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenol (0.227g 0.7 mmol), cesium carbonate (0.459 g, 1.4 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.111 g, 0.7 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 10% 2M NH₃ in MeOH:Et₂O)afforded an oil. Treatment of the oil, in acetone, with oxalic acidafforded 0.214 g (61%) ofdimethyl-[3(4-{5-[2-(2-phenoxyethyl)cyclopropyl]-[1,3,4]oxadiazol-2-yl}phenxoy)propyl]amineas the oxalate salt.

¹H NMR (DMSO-d6)

7.87 (d, 2H, J=9 Hz), 7.24–7.31 (m, 2H), 7.11 (d, 2H, J=9 Hz), 6.89–6.96(m, 3H), 4.05–4.15 (m, 4H), 3.13–3.18 (m, 2H), 2.75 (s, 6H), 2.01–2.20(m, 3H), 1.78–1.90 (m, 2H), 1.54–1.68 (m, 1H), 1.28–1.34 (m, 1H), 1.15(ddd, 1H, J=5, 6, 8 Hz). IR (CHCl₃, cm⁻¹) 3000, 1777, 1655, 1615, 1501,1302, 1250, 1224, 1175. MS (ES) m/e, 408. Anal. Calcd for C₂₄H₂₉N₃O₃: C,62.77; H, 6.28, N, 8.45. Found C, 62.58; H, 6.28; N, 8.44. Mp(° C.)=148.

Example 24Dimethyl-(3-{4-[5-(2-phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom 2-(phenylthio)ethanol

a) (2-Phenylsulfanylethoxy)acetic acid

A suspension of sodium hydride (1.15 g, 28.9 mmol) (washed once withhexane) and 2-(phenylthio)ethanol (4.45 g, 28.9 mmol) in 104 mL DMF wasstirred at room temperature for 30 minutes. Next, methyl bromoacetate(4.86 g, 31.7 mmol) was added and the stirring continued for 6.5 hours.The reaction was quenched with water then extracted twice with bothhexane followed by EtOAc. The organic phases were combined, washed twicewith water, once with brine, dried over sodium sulfate, filtered,concentrated to an oil. The oil was dissolved into 40 mL THF and 20 mLwater then treated with lithium hydroxide (2.07 g, 86.6 mmol). Thebiphasic solution was heated with stirring at 60° C. for 1 hour. Uponcooling to room temperature the reaction was quenched with 7.56 mLconcentrated HCl. The reaction was extracted with EtOAc then the organicphase was washed twice with water, once with brine, dried over sodiumsulfate, filtered, concentrated to afford an oil. Purification bychromatography on silica gel (elution with 10% MeOH containing 1%AcOH:CH₂Cl₂) afforded 0.903 g (15%) of (2-phenylsulfanylethoxy)aceticacid.

¹H NMR (DMSO-d6)

7.29–7.36 (m, 4H), 7.16–7.24 (m, 1H), 3.77 (s, 2H), 3.63 (t, 2H, J=7Hz), 3.14 (t, 2H, J=7 Hz).

IR (CHCl₃, cm⁻¹) 3051, 1603, 1481, 1440, 1428, 1409, 1116.

MS (ES) m/e, 211. Anal. Calcd for C₁₀H₁₂O₃S: C, 56.58; H, 5.70. Found C,52.81; H, 5.54.

b) 4-Hydroxybenzoic acid N′-[2-(2-phenylsulfanylethoxy]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from (2-Phenylsulfanylethoxy)aceticacid (0.800 g, 3.8 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(0.932 g, 3.8 mmol) and 4-hydroxybenzoic hydrazide (0.573 g, 3.8 mmol)to afford the title compound as a crude mixture. Purification by HPLC onsilica gel (elution with a linear gradient of 2 to 5% MeOH:CHCl₃)afforded 0.183 g (14%) of 4-hydroxybenzoic acidN′-[2-(2-phenylsulfanylethoxy]hydrazide.

¹H NMR (DMSO-d6)

10.07 (bs, 2H), 9.68 (bs, 1H), 7.74 (d, 2H, J=9 Hz), 7.30–7.40 (m, 4H),7.16–7.22 (m, 1H), 6.81 (d, 2H, J=8 Hz), 4.04 (s, 2H), 3.71 (t, 2H, J=7Hz), 3.23 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3209, 1692, 1640, 1608, 1507,1439, 1281, 1236, 1173, 1127, 850, 742, 692. MS (ES) m/e, 347, 345.Anal. Calcd for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09. Found C, 58.52;H, 4.96; N, 8.01.

c) 4-[5-(2-Phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-Hydroxybenzoic acidN′-[2-(2-phenylsulfanylethoxy]hydrazide (0.161 g, 0.7 mmol),triphenylphosphine (0.244 g, 0.9 mmol), triethyl amine (0.094 g, 0.9mmol) and carbon tetrabromide (0.308 g, 0.9 mmol) to afford the titlecompound as a crude mixture. Purification by radial chromatography onsilica gel (elution with 75% EtOAc:hexane) afforded 0.135 g (88%) of4-[5-(2-Phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.35 (bs, 1H), 7.82 (d, 2H, J=9 Hz), 7.25–7.36 (m, 4H), 7.14–7.20 (m,1H), 6.95 (d, 2H, J=9 Hz), 4.78 (s, 2H), 3.73 (t, 2H, J=7 Hz), 3.20 (t,2H, J=7 Hz).

IR (KBr, cm⁻¹) 3586, 3005, 1615, 1603, 1505, 1498, 1482, 1440, 1283,1171, 1112, 1085, 843. MS (ES) m/e, 329, 327. Anal. Calcd forC₁₇H₁₆N₂O₃S: C, 62.18; H, 4.91; N, 8.53. Found C, 61.90; H, 4.88; N,8.35.

d)Dimethyl-(3-{4-[5-(2-phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(2-phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol (0.114g 0.4 mmol), cesium carbonate (0.226 g, 0.7 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.055 g, 0.4 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 10% 2M NH₃ in MeOH:CHCl₃)followed by treatment of the isolated material with oxalic acid inacetone afforded 0.130 g (74%) ofDimethyl-(3-{4-[5-(2-phenylsulfanylethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amineas the oxalate salt.

¹H NMR (DMSO-d6)

7.93 (d, 2H, J=7 Hz), 7.25–7.36 (m, 4H), 7.13–7.20 (m, 3H), 4.80 (s,2H), 4.15 (t, 2H, J=6 Hz), 3.74 (t, 2H, J=6 Hz), 3.14–3.23 (m, 4H), 2.76(s, 6H), 2.09–2.18 (m, 2H). IR (KBr, cm⁻¹) 3432, 3037, 2930, 2874, 1726,1611, 1496, 1258, 1109, 742. MS (ES) m/e, 414. Anal. Calcd forC₂₂H₂₇N₃O₃S.C₂H₂O₄: C, 57.24; H, 5.80; N, 8.34. Found C, 57.14; H, 5.71;N, 8.27. Mp(° C.)=143.

Example 25 Preparation of(3-{4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadizol-2-yl]phenoxy}propyl)dimethylaminefrom 2-Chloromethylbenzoxazole

a) (Benzooxazol-2-ylmethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from 2-Chloromethylbenzoxazole (1.57g, 9.4 mmol), methylthio-glycolate (0.994 g, 9.4 mmol), and sodiumhydride (0.375 g, 9.4 mmol) to afford the title compound as a crudemixture. Purification by crystallization with Et2O afforded 1.12 g (54%)of (Benzo-oxazol-2-ylmethylsulfanyl)acetic acid.

¹H NMR DMSO-d6)

12.71 (bs, 1H), 7.68–7.75 (m, 2H), 7.34–7.43 (m, 2H), 4.14 (s, 2H), 3.45(s, 2H). IR (KBr, cm⁻¹) 2933, 2542, 1725, 1606, 1571, 1454, 1236, 1191,1133, 840, 767. MS (ES) m/e, 224. Anal. Calcd for C₁₀H₉NO₃S: C, 53.80;H, 4.06; N, 6.27. Found C, 53.53; H, 4.02; N, 6.17.

b) 4-Hydroxybenzoicacid-N′-[2-benzooxazol-2-ylmethylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from(benzooxazol-2-ylmethylsulfanyl)acetic acid (0.822 g, 3.7 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.911 g, 3.7 mmol) and4-hydroxybenzoic hydrazide (0.560 g, 3.7 mmol) to afford the titlecompound as a crude material. Purification by HPLC on silica gel(elution with a linear gradient of 2 to 10% 2M NH₃ in MeOH:CHCl₃)afforded 0.190 g (14%) of 4-hydroxy benzoicacid-N′-[2-benzooxazol-2-ylmethylsulfanyl)acetyl]hydrazide as a whitefoam.

¹H NMR (DMSO-d6)

10.27 (bs, 1H), 9.83 (bs, 1H), 9.38 (bs, 1H), 7.71–7.86 (m, 3H),6.68–6.94 (m, 5H), 4.20 (s, 2H), 3.61 (s, 2H). IR (KBr, cm⁻¹) 3208,1658, 1612, 1598, 1497, 1456, 1368, 1282, 1239, 1172, 843, 752. MS (ES)m/e, 358, 356. Anal. Calcd for C₁₇H₁₅N₃O₄S: C, 57.13; H, 4.23; N, 11.76.Found C, 56.82; H, 4.08; N, 11.71.

c)4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-[2-benzooxazol-2-ylmethylsulfanyl)acetyl]hydrazide (0.190 g, 0.5mmol), triphenylphosphine (0.279 g, 1.1 mmol), triethyl amine (0.108 g,1.1 mmol) and carbon tetrabromide (0.353 g, 1.1 mmol) to afford thetitle compound as a crude mixture. Purification by radial chromatographyon silica gel (elution with 50% EtOAc:hexane) afforded 0.150 g of4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenolalong with triphenylphosphine as a contaminant.

¹H NMR (DMSO-d6)

10.29 (bs, 1H), 7.52 (m, 4H), 7.30–7.39 (m, 2H), 6.88–6.93 (m, 2H), 4.24(d, 4H). IR (KBr, cm⁻¹) 3227, 1609, 1561, 1497, 1452. MS (ES) m/e, 340,338. Anal. Calcd for C₁₇H₁₃N₃O₃S: C, 60.17; H, 3.86; N, 12.38. Found C,63.51; H, 4.23; N, 9.32.

d) (3-{4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadizol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.131 g, 0.4 mmol), cesium carbonate (0.252 g, 0.8 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.061 g, 0.4 mmol) toafford the title compound as a crude material. Purification by radialchromatography on silica gel (elution with 10% 2M NH3 in MeOH:CHCl₃)followed by treatment of the isolated, material with oxalic acid inacetone afforded 0.026 g (13%) of(3-{4-[5-(Benzooxazol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadizol-2-yl]phenoxy}propyl)dimethylamineas the oxalate salt.

¹H NMR DMSO-d6)

7.81 (d, 2H, J=9 Hz), 7.60–7.64 (m, 2H), 7.29–7.38 (m, 2H), 7.10 (d, 2H,J=9 Hz), 4.25 (d, 4H), 4.14 (t, 2H, J=6 Hz), 3.15–3.20 (m, 2H), 2.77 (s,6H), 2.08–2.17 (m, 2H). IR (KBr, cm⁻¹) 3007, 1777, 1656, 1614, 1500,1455, 1302, 1254, 1176, 839. MS (ES) m/e, 425. Anal. Calcd forC₂₂H₂₄N₄O₃S.C₂H₂O₄: C, 56.02; H, 5.09; N, 10.89. Found C, 55.28; H,4.84; N, 10.74. Mp(° C.)=120.

Example 26 Preparation of(3-{4-[5-Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylaminefrom 2-Bromomethylbenzofuran

a) (Benzofuran-2-ylmethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from 2-Bromomethylbenzofuran (3.34g, 15.8 mmol), methylthioglycolate (2.02 g, 19.0 mmol), and sodiumhydride (0.760 g, 19.0 mmol) to afford the title compound as a crudematerial. Purification by HPLC on silica gel (elution with a lineargradient of 2 to 10% MeOH:CHCl₃) afforded 1.46 g of(Benzofuran-2-ylmethylsulfanyl)acetic acid along with other coelutingimpurities. Material was taken on to next step without furtherpurification.

b) 4-Hydroxybenzoicacid-N′-[2-benzofuran-2-ylmethylsulfanyl)acetyl]hydrazide

To a solution of benzofuran-2-ylmethylsulfanyl)acetic acid (1.46 g, 6.6mmol) in 100 mL THF stirring at room temperature was added1,1′-carbonyldiimidazole (1.07 g, 6.6 mmol). The reaction was heated at60° C. for one hour. After cooling to room temperature, the mixture wastreated with and 4-hydroxybenzoic hydrazide (1.50 g, 9.9 mmol). Afterstirring for approximately 4 hours the reaction was concentrated to asolid material. The material was partitioned between EtOAc and 1N HCl.The phases were separated and the organic phase was washed twice with 1NHCl, brine, dried over sodium sulfate, filtered, concentrated to affordan oil. Treatment of the oil with CHCl₃ followed by sonication afforded0.854 g (36%) of 4-Hydroxybenzoicacid-N′-[2-benzofuran-2-ylmethylsulfanyl)acetyl]hydrazide as afilterable solid.

¹H NMR (DMSO-d6)

10.02 (bs, 1H), 7.76 (d, 2H, J=8 Hz), 7.53–7.61 (m, 2H), 7.20–7.31 (m,2H), 6.83 (m, 3H), 4.09 (s, 2H), 3.27 (s, 2H). IR (KBr, cm⁻¹) 3296,3211, 3007, 1687, 1625, 1584, 1515, 1452, 1281, 1173, 956, 745. MS (ES)m/e, 357, 355. Anal. Calcd for C₁₈H₁₆N₂O₄S: C, 60.66; H, 4.53; N, 7.86.Found C, 58.53; H, 4.43; N, 7.93.

c)4-[5-(benzofuran-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-[2-benzofuran-2-ylmethylsulfanyl)acetyl]hydrazide (0.753 g, 2.1mmol), triphenylphosphine (0.665 g, 2.5 mmol), triethyl amine (0.256 g,2.5 mmol) and carbon tetrabromide (0.841 g, 2.5 mmol) to afford thetitle compound as a crude material. Purification by radialchromatography on silica gel (elution with 75% EtOAc:hexane) afforded0.550 g (77%) of 4-[5-(benzofuran-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol as an oil that slowlycrystallized out.

¹H NMR (DMSO-d6)

10.29 (s, 1H), 7.72 (d, 2H, J=8 Hz), 7.46–7.57 (m, 2H), 7.17–7.28 (m,2H), 6.79 (s, 11H), 6.79 (s, 1H), 4.10 (s, 2H), 4.08 (s, 2H). IR (KBr,cm⁻¹) 3429, 3053, 2936, 1611, 1595, 1575, 1452, 1293, 1176, 1097, 953,844, 757. MS (ES) m/e, 339, 337. Anal. Calcd for C₁₈H₁₄N₂O₃S: C, 63.89;H, 4.17; N, 8.28. Found C, 63.05; H, 4.34; N, 7.26.

d)(3-{4-[5-Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(Benzofuran-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol(0.510 g, 1.5 mmol), cesium carbonate (0.982 g, 3.0 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.238 g, 1.5 mmol) toafford the title compound as a crude material. Purification by radialchromatography on silica gel (elution with 10% 2M NH₃ in MeOH:CHCl₃)followed by treatment of the isolated material with oxalic acid inacetone afforded 0.364 g (47%) of(3-{4-[5-Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamineas the oxalate salt.

¹H NMR (DMSO-d6)

7.83 (d, 2H, J=9 Hz), 7.45–7.56 (m, 2H), 7.17–7.27 (m, 2H), 7.10 (d, 2H,J=9 Hz), 6.79 (s, 1H), 4.09–4.16 (m, 6H), 3.15–3.20 (m, 2H), 2.77 (s,6H), 2.09–2.18 (m, 2H). IR (KBr, cm⁻¹) 1615, 1500, 1255, 1175, 949, 754,707. MS (ES) m/e, 424. Anal. Calcd for C₂₃H₂₅N₃O₃S.C₂H₂O₄: C, 58.47; H,5.30; N, 8.18. Found C, 58.08; H, 5.22; N, 8.08. Mp(° C.)=144.

Example 27 Preparation of(3-{4-[5-Benzo[b]thiophene-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylaminefrom 2-bromomethylbenzo[b]thiophene

a) (Benzo[b]thiophene-2-ylmethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from 2-bromomethylbenzo[b]thiophene(2.21 g, 9.7 mmol), methylthioglycolate (1.03 g, 9.7 mmol), and sodiumhydride (0.389 g, 9.7 mmol) to afford the title compound as a crudemixture. Purification by HPLC on silica gel (elution with a lineargradient of 2 to 10% MeOH:CHCl₃) followed by crystallization of theisolated material from Et₂O:hexane afforded 1.16 g (50%) of(benzo[b]thiophene-2-ylmethylsulfanyl)acetic acid.

¹H NMR (DMSO-d6)

12.65 (bs, 1H), 7.89–7.92 (m, 1H), 7.76–7.80 (m, 1H), 7.29–7.38 (m, 3H),4.16 (s, 2H), 3.24 (s, 2H). IR (CHCl₃, cm⁻¹) 3010, 2917, 2673, 2568,1710, 1458, 1436, 1297, 1132. MS (ES) m/e, 237. Anal. Calcd forC₁₁H₁₀O₂S₂: C, 55.44; H, 4.23. Found C, 55.41; H, 4.13.

b) 4-Hydroxybenzoicacid-N′-[2-benzo[b]thiophen-2-ylmethylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from(benzo[b]thiophene-2-ylmethylsulfanyl)acetic acid (1.00 g, 4.2 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.04 g, 4.2 mmol) and4-hydroxybenzoic hydrazide (0.638 g, 4.2 mmol) to afford the titlecompound. The resultant crystals that had formed upon concentration ofthe crude material were collected by filtration to afford 0.982 g (63%)of 4-Hydroxybenzoicacid-N′-[2-benzo[b]thiophen-2-ylmethylsulfanyl)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.17 (bs, 1H), 10.09 (bs, 1H), 9.99 (bs, 1H), 7.89–7.93 (m, 1H),7.75–7.79 (m, 3H), 7.22–7.38 (m, 3H), 6.82 (d, 2H, J=9 Hz), 4.24 (s,2H), 3.24 (s, 2H).

IR (KBr, cm⁻¹) 3311, 3200, 3004, 1685, 1624, 1610, 1585, 1547, 1518,1495, 1331, 1285, 1234, 1175, 1109, 747. MS (ES) m/e, 373. Anal. Calcdfor C₁₈H₁₈N₂O₃S₂: C, 57.73; H, 4.84; N, 7.48. Found C, 57.95; H, 4.09;N, 7.29.

c)4-[5-(benzo[b]thiophene-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-[2-benzo[b]thiophen-2-ylmethylsulfanyl)acetyl]hydrazide (0.611g, 1.6 mmol), triphenylphosphine (0.860 g, 3.3 mmol), triethyl amine(0.332 g, 3.3 mmol) and carbon tetrabromide (1.09 g, 3.3 mmol) to affordthe title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 50% EtOAc:hexane) followed bythe filtration of the resultant crystals in the eluent afforded 0.208 g(36%) of4-[5-(benzo[b]thiophene-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.29 (s, 1H), 7.87–7.90 (m, 1H), 7.72–7.78 (m, 3H), 7.28–7.37 (m, 3H),6.92 (d, 2H, J=9 Hz), 4.22 (s, 2H), 4.04 (s, 2H). IR (KBr, cm⁻¹) 3160,2982, 2932, 1609, 1599, 1565, 1498, 1457, 1282, 1221, 1175, 742. MS (ES)m/e, 355. Anal. Calcd for C₁₅H₁₆N₂O₃S₂: C, 60.65; H, 4.52; N, 7.86.Found C, 61.72; H, 4.26; N, 7.31.

d)(3-{4-[5-Benzo[b]thiophene-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(benzo[b]thiophene-2-ylmethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]phenol(0.178 g, 0.5 mmol), cesium carbonate (0.325 g, 1.0 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.079 g, 0.5 mmol) toafford the title compound as a crude mixture. Purification by radialchromatography on silica gel (elution with 10% 2M NH3 in MeOH:CHCl₃)followed by crystallization of the isolated material from Et2O afforded0.115 g (52%) of(3–1{4[5-benzo[b]thiophene-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine.

¹H NMR (DMSO-d6)

7.74–7.89 (m, 4H), 7.27–7.36 (m, 3H), 7.08 (d, 2H, J=9 Hz), 4.23 (s,2H), 4.05–4.11 (m, 4H), 2.36 (t, 2H, J=7 Hz), 2.15 (s, 6H), 1.88 (m,2H). IR (KBr, cm⁻¹) 3432, 2940, 2814, 2761, 1587, 1616, 1563, 1500,1469, 1428, 1305, 1256, 1177, 1153, 1088, 1051, 821, 740, 728. MS (ES)m/e, 438. Anal. Calcd for C₂₃H₂₅N₃O₃S₂: C, 62.15; H, 5.62; N, 9.24.Found C, 62.84; H, 5.73; N, 9.56. Mp(° C.)=93.

Example 28 Preparation ofDimethyl-(3-{4-[5(naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom 2-Bromomethylnaphthalene

a) (Naphthalen-2ylmethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from 2-bromomethylnaphthalene (1.86g, 8.4 mmol), methylthioglycolate (0.982 g, 9.3 mmol), and sodiumhydride (0.370 g, 9.3 mmol) to afford the title compound as a crudemixture. Crystallization from Et₂O afforded 1.01 g (52%) of(Naphthalen-2ylmethylsulfanyl)acetic acid.

¹H NMR (DMSO-d6)

12.60 (bs, 1H), 7.86–7.91 (m, 3H), 7.78 (s, 1H), 7.46–7.54 (m, 3H), 3.98(s, 2H), 3.13 (s, 2H).

IR (CHCl₃, cm⁻¹) 3059, 3019, 3010, 1709, 1601, 1510, 1422, 1295, 1230,1126, 820. MS (ES) m/e, 231. Anal. Calcd for C₁₃H₁₂O₂S: C, 67.22; H,5.21. Found C, 73.11; H, 4.83.

b) 4-Hydroxybenzoicacid-N′-[2-(naphthalen2-ylmethylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from(Naphthalen-2-ylmethylsulfanyl)acetic acid (1.00 g, 4.3 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.06 g, 4.3 mmol) and4-hydroxybenzoic hydrazide (0.655 g, 4.3 mmol) to afford the titlecompound. The resultant crystals that had formed upon concentration ofthe crude material were collected by filtration to afford 0.761 g (48%)of 4-hydroxybenzoicacid-N′-[2-(naphthalen-2-ylmethylsulfanyl)acetyl]hydrazide

¹H NMR (DMSO-d6)

10.18 (bs, 1H), 10.09 (bs, 1H), 9.99 (bs, 1H), 7.83–7.97 (m, 4H), 7.77(d, 2H, J=9 Hz), 7.45–7.55 (m, 3H), 6.83 (d, 2H, J=9 Hz), 4.06 (s, 2H),3.15 (s, 2H). IR (KBr, cm⁻¹) 3206, 3055, 3005, 1688, 1622, 1610, 1584,1549, 1517, 1495, 1289, 1234, 1173, 750. MS (ES) m/e, 367, 365. Anal.Calcd for C₂₀H₁₈N₂O₃S: C, 65.56; H, 4.95; N, 7.64. Found C, 65.74; H,4.69; N, 7.58.

c)4-[5-(Naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-[2-(naphthalen-2-ylmethylsulfanyl)acetyl]hydrazide (0.562 g, 1.5mmol), triphenylphosphine (0.805 g, 3.1 mmol), triethyl amine (0.310 g,3.1 mmol) and carbon tetrabromide (1.02 g, 3.1 mmol) to afford the titlecompound as a crude mixture. Attempts to purify material by silica gelradial chromatography failed. Material taken on to next step withoutfurther purification.

d)Dimethyl-(3-{4-[5(naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(Naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.534 g, 1.5 mmol), cesium carbonate (0.999 g, 3.1 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.242 g, 1.5 mmol) toafford the title compound. Purification by radial chromatography onsilica gel (elution with 10% 2M NH₃ in MeOH:CHCl₃) afforded 0.155 g ofthe title compound as a solid. This material was dissolved into Et2Othen treated with a solution of EtOH that was treated with acetylchloride (0.030 mL, 0.43 mmol). The resultant precipitate was collectedby filtration to afford 0.103 g (16%) ofdimethyl-(3-{4-[5(naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.89–7.82 (m, 6H), 7.46–7.53 (m, 3H), 7.11 (d, 2H, J=9 Hz), 4.16 (t, 2H,J=6 Hz), 4.05 9s, 2H), 3.99 (s, 2H), 3.21 (m, 2H), 2.78 (s, 6H),2.13–2.22 (m, 2H).

IR (KBr, cm⁻¹) 3428, 3015, 2956, 2605, 2482, 1613, 1567, 1498, 1486,1473, 1473, 1428, 1392, 1309, 1260, 1243, 1182, 1088, 1055, 941, 832,752, 734. MS (ES) m/e, 434. Anal. Calcd for C₂₅H₂₇N₃O₂S.HCl: C, 63.88;H, 6.00; N, 8.94. Found C, 63.05; H, 5.88; N, 8.65. Analytical HPLC:100% Purity. Mp(° C.)=194.

Example 29 Preparation ofDimethyl-(3-{4-[5(naphthalen-1-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom 1-bromomethylnaphthalene

a) (Naphthalen-2ylmethylsulfanyl)acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 17b, from 1-bromomethylnaphthalene (10.71g, 48.4 mmol), methylthio glycolate (3.57 g, 38.3 mmol), and sodiumhydride (3.10 g, 77.5 mmol) to afford the title compound as a crudemixture. Purification by flash filtration chromatography on silica gel(elution with 3×500 mL CH₂Cl₂, 3×500 mL 10% MeOH:CH₂Cl₂) afforded 6.76 g(75%) of (naphthalen-1yl-methylsulfanyl)acetic acid.

¹H NMR (DMSO-d6)

12.68 (bs, 11H), 8.16–8.20 (m, 11H), 7.90–7.97 (m, 1H), 7.83–7.88 (m,1H), 7.50–7.60 (m, 2H), 7.41–7.48 (m, 2H), 4.30 (s, 2H), 3.20 (s, 2H).IR (KBr, cm⁻¹) 3065, 3050, 3001, 2928, 1709, 1597, 1512, 1426, 1399,1295, 802. MS (EI) m/e, 232

b) 4-Hydroxybenzoicacid-N′-[2-(naphthalen2-ylmethylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from(Naphthalen-lylmethylsulfanyl)acetic acid (1.77 g, 7.6 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.89 g, 7.6 mmol) and4-hydroxybenzoic hydrazide (1.16 g, 7.6 mmol) to afford the titlecompound as a crude mixture. Crystallization from MeOH:Et2O afforded1.57 g (56%) of 4-hydroxybenzoicacid-N′-[2-(naphthalen-1-ylmethylsulfanyl)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.24–10.04 (m, 3H), 8.22 (d, 1H, J=8 Hz), 7.94 (d, 1H, J=8 Hz), 7.85(d, 1H, J=8 Hz), 7.78 (d, 2H, J=9 Hz), 7.43–7.61 (m, 4H), 6.83 (d, 2H,J=9 Hz), 4.40 (s, 2H), 3.22 (s, 2H). IR (KBr, cm⁻¹) 3364, 3173, 3017,1693, 1654, 1610, 1571, 1511, 1495, 1294, 1285, 1237, 1175, 778. MS (ES)m/e, 367, 365. Anal. Calcd for C₂₀H₁₈N₃O₃S: C, 65.56; H, 4.95; N, 7.64.Found C, 63.99; H, 4.74; N, 7.33.

c)4-[5-(Naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, using 4-hydroxybenzoicacid-N′-[2-(naphthalen-1-ylmethylsulfanyl)acetyl]hydrazide (0.898 g, 2.5mmol), triphenylphosphine (1.93 g, 7.4 mmol), triethyl amine (0.744 g,7.4 mmol) and carbon tetrabromide (2.44 g, 7.4 mmol) to afford the titlecompound. Purification by silica gel flash filtration (elution with 50%Et₂O:hexane followed by Et₂O) afforded 0.420 g (49%) of4-[5-(Naphthalen-1-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenolas a white solid.

¹H NMR DMSO-d6)

10.31 9s, 1H), 8.13–8.17 (m, 1H), 7.91–7.95 (m, 1H), 7.84 (d, 1H, J=8Hz), 7.77 (d, 2H, J=8 Hz), 7.38–7.57 (m, 4H), 6.94 (d, 2H, J=8 Hz), 4.35(s, 2H), 4.01 (s, 2H). IR (KBr, cm⁻¹) 3057, 1613, 1594, 1577, 1446,1293, 1177, 773. MS (ES) m/e, 349, 347. Anal. Calcd for C₂₀H₁₆N₂O₂S: C,68.95; H, 4.63; N, 8.04. Found C, 67.72; H, 4.54; N, 7.74.

d)Dimethyl-(3-{4-[5(naphthalen-1-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(Naphthalen-1-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.400 g, 1.1 mmol), cesium carbonate (0.748 g, 2.3 mmol) and3-chloro-N,N-dimethylpropyl amine hydrochloride (0.181 g, 1.1 mmol) toafford the title compound. Purification by silica gel radialchromatography (elution with 5% 2M NH₃ in MeOH:CHCl₃) afforded 0.374 gof the title compound as a solid. Crystallization from Et2O afforded0.374 g (75%) ofDimethyl-(3-{4-[5(naphthalen-1-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6) δ 8.16–8.13 (m, 1H), 7.92–7.95 (m, 1H), 7.84–7.88 (m,3H), 7.41–7.57 (m, 4H), 7.12 (d, 2H, J=9 Hz), 4.36 (s, 2H), 4.10 (t, 2H,J=7 Hz), 2.15 (s, 6H), 1.84–1.93 (m, 2H). IR (KBr, cm⁻¹) 1614, 1500,1469, 1257, 1175, 839. MS (ES) m/e, 434. Anal. Calcd for C₂₅H₂₇N₃O₂S: C,69.26; H, 6.28; N, 9.69. Found C, 68.35; H, 6.16; N, 9.59. Mp(° C.)=96.

Example 30 Preparation of Dimethyl-(3-{4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine from 3-Phenylpropylmercaptan

a) 4-Hydroxybenzoic acid N′-[2(3-phenylpropylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from (3-phenyl propylsulfanyl)aceticacid (2.00 g, 9.5 mmol), 4-hydroxy benzoic hydrazide (1.45 g, 9.5 mmol)and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.35 g, 9.5 mmol) toafford the title compound as a crude mixture. Crystallization frommethanol and diethyl ether afforded 2.15 g (66%) of 4-hydroxybenzoicacid N′-[2(3-phenyl propyl sulfanyl)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.02–10.13 (m, 2H), 9.94–9.97 (bs, 1H), 7.74 (d, 2H, J=8 Hz), 7.14–7.31(m, 5H), 6.81 (d, 2H, J=9 Hz), 3.21 (s, 2H), 2.63–2.69 (m, 4H),1.80–1.92 (m, 2H).

IR (KBr, cm⁻¹) 3311, 3208, 2859, 1695, 1625, 1609, 1585, 1517, 1495,1284, 1175, 1115, 848, 694, 567. MS (ES) m/e, 345, 343. Anal. Calcd forC₁₈H₂₀N₂O₃S: C, 62.77; H, 5.85; N, 8.13. Found C, 62.37; H, 5.86; N,8.03.

b) 4-[5(3-Phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-[2(3-phenylpropyl sulfanyl)acetyl]hydrazide (1.94 g, 5.6 mmol),triphenyl phosphine (2.95 g, 11.3 mmol), triethylamine (2.05 g, 20.2mmol) and carbon tetrabromide (3.55 g, 23.1 mmol) to afford the titlecompound as a crude material. Purification by flash filtrationchromatography on silica gel (elution with 50% acetone:hexane) followedby crystallization of the isolated product from EtOH afforded 0.973 g(53%) of 4-[5(3-phenylpropyl sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.31 (s, 1H), 7.78 (d, 2H, J=9 Hz), 7.14–7.27 (m, 5 Hz), 6.94 (d, 2H,J=9 Hz), 4.07 (s, 2H), 2.60–2.67 (m, 4H), 1.79–1.89 (m, 2H). IR (KBr,cm⁻¹) 3143, 3024, 2938, 1611, 1601, 1499, 1232. MS (ES) m/e, 327, 325.Anal. Calcd for C₁₈H₁₈N₂O₂S: C, 66.23; H, 5.56; N, 8.58. Found C, 65.87;H, 5.47; N, 8.44.

c) Dimethyl-(3-{4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from 4-[5(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol (0.800 g, 2.5 mmol), sodiumhydride (0.225 g, 5.6 mmol), and 3-chloro-N,N-dimethylpropylamine HCl(0.426 g, 2.7 mmol) to afford the title compound as a crude material.Purification by radial chromatography on silica gel (elution with 10% 2MNH₃ IN MeOH:CHCl₃) afforded 0.602 g of an oil. The oil was dissolved indiethyl ether. To this solution was added dropwise, a solution of EtOHin Et2O that was treated with 0.116 mL acetyl chloride. The resultantprecipitate was collected by filtration to afford 0.533 g (50%) ofdimethyl-(3-{4-[5-(3-phenylpropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine as the hydrochloridesalt.

¹H NMR (DMSO-d6)

7.90 (d, 2H, J=9 Hz), 7.22–7.27 (m, 2H), 7.13–7.18 (m, 5H), 4.17 (t, 2H,J=6 Hz), 4.09 (s, 2H), 3.19–3.21 (m, 2H), 2.78 (s, 6H), 2.60–2.67 (m,4H), 2.13–2.22 (m, 2H), 1.79–1.89 (m, 2H). IR (CHCl₃, cm⁻¹) 2970, 2337,1615, 1570, 1500, 1474, 1254, 1176. MS (ES) m/e, 412. Anal. Calcd forC₂₃H₂₉N₃O₂S.HCl: C, 61.66; H, 6.75; N, 9.38. Found C, 61.30; H, 6.76; N,9.13. Mp(° C.)=148.

Example 31 Preparation ofDimethyl-(3-{4-[5-(2-phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom 2-(Phenoxyethoxy)acetic acid

a) 4-Hydroxybenzoic acid N′-[2-(2-phenoxyethoxy)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 2-(phenoxyethoxy)acetic acid(2.0 g, 10.2 mmol), 4-hydroxybenzoic hydrazide (1.55 g, 10.2 mmol) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.52 g, 10.2 mmol) toafford the title compound as a crude mixture. Purification by HPLC onsilica gel (elution with a linear gradient of 0 to 10% MeOH:CHCl₃ over athirty minute period) followed by crystallization of the isolatedmaterial from MeOH:Et₂O afforded 1.02 g (30%) of 4-hydroxybenzoic acidN′-[2-(2-phenoxyethoxy)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.08 (bs, 2H), 9.76 (bs, 1H), 7.74 (d, 2H, J=9 Hz), 7.24–7.32 (m, 2H),6.91–6.97 (m, 3H), 6.81 (d, 2H, J=9 Hz), 4.16–4.19 (m, 2H), 4.11 (s,2H), 3.85–3.89 (m, 2H). IR (KBr, cm⁻¹) 3229, 1695, 1647, 1627, 1609,1588, 1574, 1507, 1498, 1246, 1140, 755. MS (ES) m/e, 331, 329. Anal.Calcd for C₁₇H₁₈N₂O₅: C, 61.81; H, 5.49; N, 8.48. Found C, 61.26; H,5.51; N, 8.46.

b) 4-[5-(2-Phenoxyethoxymethyl)-[1,3,4]-oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoic acidN′-[2-(2-phenoxyethoxy) acetyl]hydrazide (0.961 g, 2.9 mmol),triphenylphosphine (1.53 g, 5.8 mmol), triethylamine (1.06 g, 10.5 mmol)and carbon tetrabromide (1.83 g, 11.9 mmol) to afford the title compoundas a crude mixture. Purification by flash filtration chromatography onsilica gel (elution with 50% acetone:hexane) followed by crystallizationof the isolated product from EtOH afforded 0.473 g (52%) of4-[5-(2-phenoxyethoxymethyl)-[1,3,4]-oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.32 (bs, 1H), 7.81 (d, 2H, J=9 Hz), 7.23–7.30 (m, 2H), 6.89–6.97 (m,5H), 4.85 (s, 2H), 4.13–4.16 (m, 2H), 3.89–3.92 (m, 2H). IR (KBr, cm⁻¹)3120, 1609, 1600, 1497, 1218, 1244, 1251, 1116, 753. MS (ES) m/e, 313,311. Anal. Calcd for C₁₇H₁₆N₂O₄: C, 65.38; H, 5.16; N, 8.97. Found C,65.00; H, 5.10; N, 8.65.

c) Preparation ofDimethyl-(3-{4-[5-(2-phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from 4-[5-(2-phenoxyethoxymethyl)-[1,3,4]-oxadiazol-2-yl]phenol (0.420 g, 1.3 mmol), sodiumhydride (0.124 g, 3.1 mmol), and 3-chloro-N,N-dimethylpropylamine HCl(0.234 g, 1.5 mmol) to afford the title compound as a crude mixture.Crystallization from hexane:Et₂O afforded 0.321 g (60%) ofdimethyl-(3-{4-[5-(2-phenoxyethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6) δ 7.90 (d, 2H, J=9 Hz), 7.24–7.29 (m, 2H), 7.12 (d, 2H,J=9 Hz), 6.89–6.94 (m, 3H), 4.86 (s, 2H), 4.07–4.16 (m, 4H), 3.90–3.93(m, 2H), 2.36 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.83–1.92 (m, 2H). IR(CHCl₃, cm⁻¹) 2948, 2824, 2777, 1614, 1600, 1589, 1499, 1469, 1302,1256, 1175, 1087, 839. MS (FD) m/e, 397. Anal. Calcd for C₂₂H₂₇N₃O₄: C,66.48; H, 6.85; N, 10.57. Found C, 66.10; H, 6.83; N, 10.44. Mp(°C.)=77.

Example 32 Preparation ofN-(3-Dimethylaminopropyl)-4-[5-(2-phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamidefrom (2-Phenoxyethylthio)acetic acid

a) 4-[5-(2-Phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from (2-phenoxyethylthio)acetic acid(2.21 g, 10.4 mmol), 1,3-dicyclohexylcarbodiimide (2.15 g, 10.4 mmol)and 4-(1H-tetrazole-5-yl)benzoic acid methyl ester (2.13 g, 104 mmol) toafford the title compound as a crude mixture. Purification by flashfiltration chromatography on silica gel (elution with 1×250 mL CH₂Cl₂,3×250 mL 50% EtOAc:hexane) afforded 0.990 g (26%) of4-[5-(2-phenoxyethoxy sulfanyl methyl)-[1,3,4]oxadiazol-2-yl]benzoicacid methyl ester as a crystalline solid. Purification of the remainingcontaminated fractions by HPLC on silica gel (elution with a lineargradient of 25 to 40% EtOAc:hexane over a thirty minute period) afforded0.841 g (22%) of 4-[5-(2-phenoxy ethoxy sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester.

¹H NMR (DMSO-d6)

8.09–8.16 (m, 4H), 7.23–7.30 (m, 2H), 6.90–6.94 (m, 3H), 4.26 (s, 2H),4.20 (t, 2H, J=6 Hz), 3.91 (s, 3H), 3.04 (t, 2H, J=6 Hz). IR (CHCl₃,cm⁻¹) 1721, 1498, 1283, 1243. MS (ES) m/e, 371. Anal. Calcd forC₁₉H₁₈N₂O₄S: C, 61.61; H, 4.90; N, 7.56. Found C, 61.54; H, 4.91; N,7.56.

b) 4-[5-(2-Phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1c, from 4-[5-(2-phenoxy ethoxy sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid methyl ester (1.00 g, 2.7mmol), and lithium hydroxide (0.194 g, 8.1 mmol) to afford 0.868 g (90%)of 4-[5-(2-phenoxyethoxy sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid as a white solid.

¹H NMR (DMSO-d6)

13.35 (bs, 1H), 8.06–8.14 (m, 4H), 7.23–7.30 (m, 2H), 6.90–6.98 (m, 3H),4.26 (s, 2H), 4.20 (t, 2H, J=6 Hz), 3.04 (t, 2H, J=6 Hz). IR (CHCl₃,cm⁻¹) 1700, 1587, 1497, 1243. MS (ES) m/e, 357, 355. Anal. Calcd forC₁₈H₁₆N₂O₄S: C, 60.66; H, 4.53; N, 7.86. Found C, 60.29; H, 4.51; N,7.80.

c) N-(3-Dimethylaminopropyl)-4-[5-(2-phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 7c, from 4-[5-(2-phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid (0.600 g, 1.68 mmol),1-hydroxybenzotriazole (0.227 g, 1.68 mmol), 4-dimethylamino pyridine(0.021 g, 0.17 mmol), 3-(dimethylamino)propyl amine (0.181 g, 1.77 mmol)and 1,3-dicyclohexyl carbodiimide (0.365 g, 1.77 mmol) to afford thetitle compound as a crude mixture. Purification by radial chromatographyon silica gel (elution with 10% 2M NH₃ in MeOH:CH₂Cl₂) followed bycrystallization of the isolated material from EtOH:Et₂O afforded 0.335 g(45%) of N-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethoxysulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzamide.

¹H NMR (DMSO-d6)

8.72 (t, 1H, J=5 Hz), 8.00–8.07 (m, 4H), 7.23–7.29 (m, 2H), 6.90–6.94(m, 3H), 4.25 (s, 2H), 4.20 (t, 2H, J=6 Hz), 3.30 (q, 2H, J=6 Hz), 3.04(t, 2H, J=6 Hz), 2.66 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.62–1.72 (m, 2H).IR (CHCl₃, cm⁻¹) 3008, 2951, 2827, 1652, 1585, 1555, 1497, 1243, 1011.MS (ES) m/e, 441, 439. Anal. Calcd for C₂₃H₂₈N₄O₃S: C, 62.70; H, 6.41;N, 12.72. Found C, 62.33; H, 6.31; N, 12.62. Mp(° C.)=96.

Example 33 Preparation ofDimethyl-(3-{4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminefrom 5-phenoxypentanoic acid

a) 4-Hydroxybenzoic acid-1V-(5-phenoxypentainoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 5-phenoxypentanoic acid (2.00g, 10.3 mmol), 4-hydroxybenzoic hydrazide (1.57 g, 10.3 mmol) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.55 g, 10.3 mmol) toafford the title compound as a crude mixture. Purification by HPLC onsilica gel (elution with a linear gradient of 0 to 10% MeOH:CHCl₃ over athirty minute period) afforded 2.03 g (60%) of 4-hydroxybenzoicacid-N′-(5-phenoxypentanoyl)hydrazide as a white foam.

¹H NMR (DMSO-d6)

10.06 (bs, 1H), 10.02 (bs, 1H), 9.75 (bs, 1H), 7.74 (d, 2H, J=9 Hz),7.21–7.31 (m, 2H), 6.87–6.95 (m, 3H), 6.81 (d, 2H, J=9 Hz), 3.98 (t, 2H,J=6 Hz), 2.24 (t, 2H, J=7 Hz), 1.62–1.83 (m, 4H). IR (KBr, cm⁻¹) 3269,1663, 1608, 1577, 1496, 1472, 1280, 1248, 848, 754. MS (ES) m/e, 329,327. Anal. Calcd for C₁₈H₂₀N₂O₄: C, 65.84; H, 6.14; N, 8.53. Found C,65.53; H, 6.19; N, 8.36.

b) 4-[5-(4-Phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoicacid-N′-(5-phenoxypentanoyl)hydrazide (1.90 g, 5.8 mmol), triphenylphosphine (11.6 g, 3.04 mmol), triethylamine (2.11 g, 20.8 mmol) andcarbon tetrachloride (3.65 g, 23.7 mmol) to afford the title compound asa crude mixture. Purification by flash filtration chromatography onsilica gel (elution with 50% acetone:hexane) followed by crystallizationof the isolated product from ethanol afforded 1.71 g (65%) of4-[5-(4-phenoxy butyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.25 (bs, 1H), 7.78–7.82 (m, 2H), 7.23–7.31 (m, 2H), 6.88–6.96 (m, 5H),4.02 (t, 2H, J=6 Hz), 2.98 (t, 2H, J=7 Hz), 1.78–1.97 (m, 4H). IR (KBr,cm⁻¹) 3061, 2935, 2870, 1611, 1601, 1499, 1283, 1245, 1229, 1174, 1035,750, 689. MS (ES) m/e, 311, 309. Anal. Calcd for C₁₈H₁₈N₂O₃: C, 69.66;H, 5.85; N, 9.03. Found C, 69.81; H, 5.85; N, 8.76.

c)Dimethyl-(3-{4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from 4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenol (0.865 g, 2.8 mmol), sodium hydride(0.256 g, 6.4 mmol), and 3-chloro-N,N-dimethyl propylamine HCl (0.485 g,3.1 mmol) to afford the title compound as a crude mixture.Crystallization from hexane:Et₂O afforded 0.769 g (70%) ofdimethyl-(3-{4-[5-(4-phenoxybutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6)

7.88 (d, 2H, J=9 Hz), 7.23–7.30 (m, 2H), 7.10 (d, 2H, J=9 Hz), 6.89–6.94(m, 3H), 4.08 (t, 2H, J=7 Hz), 4.02 (t, 2H, J=6 Hz), 2.99 (t, 2H, J=7Hz), 2.35 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.81–1.95 (m, 6H). IR (CHCl₃,cm⁻¹) 2952, 2873, 2825, 2777, 1615, 1589, 1500, 1470, 1248, 1174. MS(FD) m/e, 395. Anal. Calcd for C₂₃H₂₉N₃O₃: C, 69.85; H, 7.39; N, 10.62.Found C, 69.87; H, 7.54; N, 10.26. Mp(° C.)=78.

Example 34 Preparation of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and N-(2-aminoethyl)pyrrolidine

To a slurry of the4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid(0.054 g, 0.15 mmole), 1-hydroxybenzotriazole hydrate (0.024 g, 0.18mmole), and N-(2-aminoethyl)pyrrolidine (0.023 ml, 0.18 mmole) in 2 mldichloromethane at room temperature was added diisopropylcarbodiimide(0.047 ml, 0.30 mmole). The reaction was stirred 16 h at ambienttemperature, then polystyrene methylisocyanate (0.06 mmole) anddichloromethane were added and the reaction was stirred at roomtemperature overnight. The reaction mixture was evaporated, taken up in3 ml methanol, and purified over an SCX column (elution with 2 M ammoniain methanol) to afford 0.067 g (99%) of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide.

¹H NMR(CDCl₃) δ 8.08(d, 2H, J=9), 7.90(d, 2H, J=9), 7.26(m, 2H), 7.01(m,1H), 6.94(t, 1H, J=8), 6.88(d, 2H, J=9), 4.22(t, 2H, J=6), 4.07(s, 2H),3.57(q, 2H, J=6), 3.06(t, 2H, J=6), 2.74(t, 2H, J=6), 2.60(m, 4H),1.80(m, 4H). MS (ES) m/e, 452.19 (C₂₄H₂₈N₄O₃S).

Example 35 Preparation of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and N-(3-aminopropyl)pyrrolidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid andN-(3-aminopropyl)pyrrolidine to afford4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide.

¹H NMR(CDCl3) δ 9.29(m, 1H), 8.08(d, 2H, J=9), 7.99(d, 2H, J=9), 7.27(m,2H), 6.98(t, 1H, J=8), 6.89(d, 2H, J=7), 4.21(t, 2H, J=7), 4.07(s, 2H),3.62(q, 2H, J=6), 3.06(t, 2H, J=6), 2.74(t, 2H, J=6), 2.59(m, 4H),1.83(m, 6H).

MS (ES) m/e, 466.20. Anal. Calcd for C₂₅H₃₀N₄O₃S.0.5H₂O: C, 63.13; H,6.75; N, 11.78. Found C, 63.33; H, 6.26; N, 11.95.

Example 36 Preparation4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(4-pyrrolidin-1-yl-butyl)-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and N-(4-aminobutyl)pyrrolidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid andN-(4-aminobutyl)pyrrolidine to afford4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-N-(4-pyrrolidin-1-yl-butyl)-benzamide.

¹H NMR(CDCl₃) δ 8.25(m, 1H), 8.09(d, 2H, J=8), 7.88(d, 2H, J=8), 7.28(m,2H), 6.95(t, 1H, J=7), 6.89(d, 2H, J=8), 4.22(t, 2H, J=7), 4.07(s, 2H),3.47(q, 2H, J=7), 3.06(t, 2H, J=6), 2.48(m, 6H), 1.71(m, 8H). MS (ES)m/e, 480.22. Anal. Calcd for C₂₅H₃₀N₄O₃S.0.33H₂O: C, 64.17; H, 6.77; N,11.51. Found C, 64.16; N, 6.58; H, 11.59.

Example 37 PreparationN-[3-(4-Methyl-piperazin-1-yl)-propyl]-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and 3-(4-Methyl-piperazin-1-yl)-propylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid and3-(4-Methyl-piperazin-1-yl)-propylamine to affordN-[3-(4-Methyl-piperazin-1-yl)-propyl]-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃) δ 8.09(m, 4H), 7.26(m, 2H), 6.95(t, 1H, J=8), 6.89(d, 2H,J=9), 4.22(t, 2H, J=8), 4.07(s, 2H), 4.00(m, 1H), 3.82(m, 1H), 3.64(q,2H, J=7), 3.40(m, 1H), 3.06(t, 2H, J=6), 2.97(m, 6H), 2.51(m, 2H),2.12(m, 1H), 1.77(m, 5H). MS (ES) m/e, 495.23. Anal. Calcd forC₂₆H₃₃N₅O₃S.HCl.H₂O: C, 56.77; H, 6.60; N, 12.73. Found C, 56.71; H,6.82; N, 13.57.

Example 38 PreparationN-(1-Benzyl-piperidin-4-yl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and 1-Benzyl-piperidin-4-ylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid and1-Benzyl-piperidin-4-ylamine to affordN-(1-Benzyl-piperidin-4-yl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃) δ 8.09(d, 2H, J=9), 7.86(d, 2H, J=9), 7.31(m, 2H), 7.24(m,5H), 6.95(t, 1H, J=8), 6.89(d, 2H, J=9), 4.21(d, 1H, J=7), 4.07(s, 2H),4.03(m, 1H), 3.52(s, 2H), 3.06(t, 2H, J=7), 2.88(d, 2H, J=11), 2.14(t,2H, J=10), 2.04(d, 2H, J=13), 1.58(m, 2H). MS (ES) m/e, 528.22. Anal.Calcd for C₃₀H₃₂N₄O₃S: C, 68.16; H, 6.10; N, 10.60. Found C, 67.78; H,6.11; N, 10.53.

Example 39 PreparationN-(2-Morpholin-4-yl-ethyl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and 2-Morpholin-4-yl-ethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid and2-morpholin-4-yl-ethylamine to affordN-(2-Morpholin-4-yl-ethyl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃) δ 8.11(d, 2H, J=9), 7.90(d, 2H, J=9), 7.28(m, 2H), 6.94(t,1H, J=9), 6.89(d, 2H, J=8), 6.85(m, 1H), 4.21(t, 2H, J=7), 4.08(s, 2H),3.75(t, 4H, J=2), 3.58(q, 2H, J=6), 3.06(t, 2H, J=6), 2.63(t, 2H, J=3),2.52(m, 4H). MS (ES) m/e, 468.18. Anal. Calcd for C₂₄H₂₈N₄O₄S: C, 61.52;H, 6.02; N, 11.96. Found C, 61.36; H, 5.94; 11.95.

Example 40 PreparationN-(3-Morpholin-4-yl-propyl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and 3-Morpholin-4-yl-propylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid and3-morpholin-4-yl-propylamine to affordN-(3-Morpholin-4-yl-propyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃) δ 8.29(m, 1H), 8.12(d, 2H, J=9), 7.95(d, 2H, J=9), 7.25(m,2H), 6.95(t, 1H, J=8), 6.89(d, 2H, J=9), 4.22(t, 2H, J=6), 4.08(s, 2H),3.70(t, 4H, J=6), 3.61(q, 2H, J=5), 3.06(t, 2H, J=8), 2.58(t, 2H, J=7),2.51(m, 4H), 1.81 (m, 2H, J=6). MS (ES) m/e, 482.20. Anal. Calcd forC₂₅H₃₀N₄O₄S.2.33H₂O: C, 57.23; H, 6.66; N, 10.68. Found C, 57.12; H,5.69; N, 10.74.

Example 41 PreparationN-(3-Imidazol-1-yl-propyl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and 3-Imidazol-1-yl-propylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid and3-imidazol-1-yl-propylamine to affordN-(3-Imidazol-1-yl-propyl)-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃) δ 8.08(d. 2H, J=9), 7.85(d, 2H, J=9), 7.56(s, 1H), 7.26(m,2H), 7.07(s, 1H), 6.98(s, 1H), 6.95(t, 1H, J=8), 6.89(d, 2H, J=9),6.43(t, 1H, J=6), 4.21(t, 2H, J=7), 4.07(t, 4H, J=7), 3.51(q, 2H, J=7),3.05(t, 2H, J=7), 2.18(m, 2H, J=7). MS (ES) m/e, 463.17.

Example 42 PreparationN-(3-Dimethylamino-propyl)-N-methyl-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and N,N,N′-Trimethyl-propane-1,3-diamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid andN,N,N′-Trimethyl-propane-1,3-diamine to affordN-(3-Dimethylamino-propyl)-N-methyl-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃)

8.06(d, 2H, J=9), 7.52(d, 2H, J=9), 7.25(m, 2H), 6.94(t, 1H, J=9),6.89(d, 2H, J=9), 4.21(t, 2H, J=7), 4.07(s, 2H), 3.59(t, 1H, J=7),3.28(t, 1H, J=8), 3.08(q, 2H, J=7), 3.06(s, 1.5H), 2.96(s, 1.5H),2.36(t, 1H, J=9), 2.26(s, 3H), 2.10(m, 1H), 2.09(s, 3H), 1.85(m, 1H),1.69(m, 1H). MS (ES) m/e, 454.20. Anal. Calcd for C₂₄H₃₀N₄O₃S.0.33H₂O:C, 62.59; H, 6.71; N, 12.16. Found C, 62.44; H, 6.54; N, 12.48.

Example 43 PreparationN-[3-(ethyl-phenyl-amino)-propyl]-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamidefrom 4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoicacid and N1-Methyl-N1-phenyl-propane-1,3-diamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 34, from4-[5-(Phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid andN1-Methyl-N1-phenyl-propane-1,3-diamine to affordN-[3-(Methyl-phenyl-amino)-propyl]-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR(CDCl₃)

8.04(d, 2H, J=9), 7.84(d, 2H, J=9), 7.26(m, 4H), 6.95(t, 1H, J=8),6.87(d, 2H, J=9), 6.77(m, 3H), 6.53(t, 11H, J=7), 4.21(t, 2H, J=6),4.07(s, 2H), 3.57(q, 2H, J=7), 3.47(t, 2H, J=7), 3.06(t, 2H, J=6),2.93(s, 3H), 1.95(m, 2H, J=7). MS (ES) m/e, 502.20. Anal. Calcd forC₂₈H₃₀N₄O₃S.0.33H₂O: C, 66.12; H, 6.08; N, 11.01. Found C, 66.91; H,5.71; N, 11.03.

Example 44 Preparation of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]-oxadiazol-2-yl}-N-(3-dimethylaminopropyl)-benzamide

a)4-N′-{2-[2-(2,4-dichlorophenoxy)-ethylsulfanyl]-acetyl}-hydrazinocarbonyl)-benzoicacid methyl ester

A solution of 2-[[2-(2,4-dichlorophenoxy)ethyl]-[thio]acetic acidhydrazide (1.48 g, 5.0 mmol), terephthalic acid, monomethyl esterchloride (0.993 g, 5.0 mmol), and triethylamine (0.836 mL, 6.0 mmol) in35 mL THF was stirred at room temperature for 6 h. The resultantprecipitate was collected by filtration, washed with THF, and thefiltrate was concentrated in vacuo to afford an off-white solid, whichwas crystallized from ethanol to afford 1.94 g (85%) of4-(N′-{2-[2-(2,4-dichlorophenoxy)-ethylsulfanyl]-acetyl}-hydrazinocarbonyl)-benzoicacid methyl ester as a white solid (1156–157° C., MW 456.03).

¹H NMR (CDCl₃) δ 9.30 (d, 1H, J=6 Hz), 8.82 (d, 1H, J=6 Hz), 8.11 (d,2H, J=8 Hz), 7.84 (d, 2H, J=8 Hz), 7.36 (d, 1H, J=2 Hz), 7.17 (dd, 1H,J=2 and 9 Hz), 6.87 (d, 1H, J=9 Hz), 4.30 (t, 2H, J=6 Hz), 3.95 (s, 3H),3.59 (s, 2H), and 3.16 (t, 2H, J=6 Hz). IR KBr, cm⁻¹) 3193, 1714, 1604,1568, 1481, 1465, 1295, 1105, and 869. MS (ESI) m/e 455, 457, 459, 461.Anal. Calcd for C₁₉H₁₈Cl₂N₂O₅S: C, 49.90; H, 3.97; Cl, 15.50; N, 6.13;S, 7.01. Found C, 49.99; H, 3.98; Cl, 15.79; N, 6.15; S, 7.37.

b)4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid methyl ester

A heterogeneous mixture of4-(N′-{2-[2-(2,4-dichlorophenoxy)-ethylsulfanyl]-acetyl}-hydrazinocarbonyl)-benzoicacid methyl ester (0.228 g, 0.5 mmol), triphenylphosphine (0.265 g, 1.0mmol), triethylamine (0.251 mL, 1.8 mmol) and carbon tetrachloride(0.202 mL, 2.06 mmol) in 4 mL acetonitrile was stirred at roomtemperature for 4 h. The resultant precipitate was collected byfiltration, washed with acetonitrile and diethyl ether, and the solidwas dried in vacuo at 40° C. for 2 h to afford 0.153 g (70%) of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid methyl ester as a white solid (MP 148–152° C., MW 438.02).

¹H NMR (CDCl₃) δ 8.17 (d, 2H, J=8 Hz), 8.10 (d, 2H, J=8 Hz), 7.34 (d,1H, J=2 Hz), 7.17 (dd, 1H, J=2 and 9 Hz), 6.84 (d, 1H, J=9 Hz), 4.26 (t,2H, J=6 Hz), 4.18 (s, 2H), 3.97 (s, 3H), and 3.12 (t, 2H, J=6 Hz). IR(KBr, cm⁻¹) 2940, 1717, 1485, 1470, 1437, 1432, 1287, 1252, 1236, 1114,1062, 1010, 776, 719, and 715. MS (ES) m/e 437, 439, 441, 443. Anal.Calcd for C₁₉H₁₆Cl₂N₂O₄S: C, 51.95; H, 3.67; Cl, 16.14; N, 6.38; S,7.30. Found C, 52.32; H, 3.69; Cl, 15.86; N, 6.38; S, 7.33.

c)4-f{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid

A suspension of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid methyl ester (0.22 g, 0.5 mmol), and lithium hydroxide (0.036 g,1.5 mmol) in 3.5 mL THF and 1.5 mL H₂O was stirred at room temperaturefor 5 h. The THF was removed in vacuo, and the remaining aqueoussolution adjusted to pH 1.7 with concentrated HCl. The resultantprecipitate was collected by filtration, washed with H₂O, and dried invacuo at 40° C. to afford 0.134 g (63%) of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid as a white solid (1161–163° C., MW 424.01).

¹H NMR (DMSO-d₆) δ 13.30 (bs, 1H), 8.11 (d, 2H, J=9 Hz), 8.04 (d, 2H,J=9 Hz), 7.52 (d, 1H, J=2 Hz), 7.33 (dd, H, J=2 and 9 Hz), 7.17 (d, 1H,J=9 Hz), 4.28 (t, 2H, J=6 Hz), 4.27 (s, 2H), and 3.05 (t, 2H, J=6 Hz).IR (KBr, cm⁻¹) 2910, 2670, 2550, 1704, 1686, 1551, 1485, 1433, 1291,1262, 1072, 871, and 714. MS (ESI) m/e 423, 425, 427, 429. Anal. Calcdfor C₁₈H₁₄Cl₂N₂O₄S: C, 50.84; H, 3.32; Cl, 16.67; N, 6.59; S, 7.54.Found C, 50.78; H, 3.40; Cl, 16.83; N, 6.55; S, 7.74.

d)4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]-oxadiazol-2-yl}-N-(3-dimethylaminopropyl)-benzamide

A solution of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-benzoicacid (0.361 g, 0.85 mmol), and 1,1′-carbonyldiimidazole (0.139 g, 0.86mmol) in 10.0 mL THF was stirred at 60° C. for 0.5 h. The reactionsolution was allowed to cool to ambient temperature followed by additionof 3-(dimethylamino)propylamine (0.129 mL, 1.02 mmol), then stirred atroom temperature for 3 h. The THF was concentrated in vacuo and theresultant precipitate was collected by filtration, washed with ethylacetate and diethyl ether, and dried in vacuo at 40° C. to afford 0.25 g(57%) of4-{5-[2-(2,4-dichlorophenoxy)-ethylsulfanylmethyl]-[1,3,4]-oxadiazol-2-yl}-N-(3-dimethylaminopropyl)-benzamideas a white solid (MP 140–141° C., MW 508.11).

¹H NMR (CDCl₃) δ 8.86 (bs, 1H), 8.09 (d, 2H, J=9 Hz), 7.92 (d, 2H, J=9Hz), 7.34 (d, 1H, J=2 Hz), 7.17 (dd, 1H, J=2 and 9 Hz), 6.84 (d, 1H, J=9Hz), 4.26 (t, 2H, J=6 Hz), 4.17 (s, 2H), 3.61 (m, 2H), 3.11 (t, 2H, J=6Hz), 2.61 (m, 2H), 2.38 (bs, 6H), 1.83 (m, 2H). IR (KBr, cm⁻¹) 3335,2942, 2761, 2722, 1635, 1555, 1484, 1105, and 803. MS (ESI) m/e 507,509, 511, 513. Anal. Calcd for C₂₃H₂₆Cl₂N₄O₃S: C, 54.23; H, 5.14; Cl,13.92; N, 11.00; S, 6.29. Found C, 54.03; H, 5.15; Cl, 13.98; N, 10.98;S, 6.25.

Example 45 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfinylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

A solution of theN-(3-dimethylaminopropyl)4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide(0.044 g, 0.1 mmol) prepared in Example 32, glacial acetic acid (1.14mL, 20.0 mmol), and 3-chloroperoxybenzoic acid (0.022 g, 0.1 mmol) in 1mL of dichloromethane was stirred at room temperature for 1 h. Themixture was quenched with 3 mL saturated sodium sulfite followed byaddition of 6 mL H₂O and 1 mL dichloromethane. The resultant biphasicsolution was adjusted to pH 10.3 with 1N NaOH, the solvent layersseparated, and the aqueous phase back extracted with 6×10 mLdichloromethane. The combined dichloromethane extracts were washed withH₂O and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford 0.043 g (95%) ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfinylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas a white solid WP 112–114° C., MW 456.57). Analytical HPLC: 93%purity.

¹H NMR (CDCl₃) δ 8.88 (bs, 1H), 8.12 (d, 2H, J=8 Hz), 7.95 (d, 2H, J=8Hz), 7.30 (t, 2H, J=8 Hz), 7.01 (t, 1H, J=7 Hz), 6.93 (d, 2H, J=8 Hz),4.62 (d, 1H, J=14 Hz), 4.48 (m, 2H), 4.36 (d, 1H, J=14 Hz), 3.61 (m,2H), 3.40 (m, 2H), 2.65 (m, 2H), 2.41 (bs, 6H), and 1.86 (m, 2H). IR(KBr, cm⁻¹) 3344, 2922, 2761, 1636, 1549, 1497, 1251, and 1044. MS (ESI)m/e 457, 455. Anal. Calcd for C₂₃H₂₈N₄O₄S: C, 60.51; H, 6.18; N, 12.27;S, 7.02. Found C, 59.91; H, 6.16; N, 11.61; S, 6.50.

Example 46 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

A solution of theN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide(0.022 g, 0.05 mmol) prepared in Example 32, glacial acetic acid (0.58mL, 10.0 mmol), and 3-chloroperoxybenzoic acid (0.022 g, 0.1 mmol) in 1mL of dichloromethane was stirred at room temperature for 19 h. Themixture was quenched with 3 mL saturated sodium sulfite followed byaddition of 2 mL H₂O and 4 mL dichloromethane. The resultant biphasicsolution was adjusted to pH 10.3 with 1N NaOH, the solvent layersseparated, and the aqueous phase back extracted with 3×15 mLdichloromethane. The combined dichloromethane extracts were washed withH₂O and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford 0.017 g (73%) of a mixture composedprimarily ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideand a minor amount ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfinylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas a white solid. A solution of the preceding mixture (0.015 g, ˜0.03mmol), osmium tetroxide (2.5 weight percent solution in2-methyl-2-propanol, 0.003 mL, 0.25 □M), and 4-methylmorpholine N-oxide(0.003 g, 0.025 mmol) in 1 mL of THF and 0.5 mL dichloromethane wasstirred at room temperature for 1 h. The THF was removed in vacuo, theresultant gum redissolved in dichloromethane, washed with H₂O and brine,dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto afford 0.008 g of a black solid. Purification by columnchromatography on silica gel (isocratic elution with 8:2 CHCl₃/2.0 Mammonia in methanol) afforded 0.003 g (13%) ofN-(3-dimethylaminopropyl)-4-[5-(2-phenoxyethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white solid (MW 472.57).

¹H NMR (CDCl₃) δ 8.88 (bs, 1H), 8.11 (d, 2H, J=8 Hz), 7.95 (d, 2H, J=8Hz), 7.33 (t, 2H, J=8 Hz), 7.04 (t, 1H, J=7 Hz), 6.97 (d, 2H, J=8 Hz),4.86 (s, 2H), 4.53 (t, 2H, J=5 Hz), 3.71 (t, 2H, J=5 Hz), 3.61 (m, 2H),2.65 (m, 2H), 2.41 (bs, 6H), and 1.87 (m, 2H). MS (ES) m/e 471, 473.

Example 47 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) 3-chloropropoxy benzene

A solution of phenol (9.41 g, 0.1 M), 1-bromo-3-chloropropane (15.74 g,0.1 M) and potassium carbonate (13.8 g, 0.1 M) in 150 mL of DMF wasstirred at room temperature for 48 h, then sonicated at 50–60° C. for 12h. The DMF was removed in vacuo, the residue diluted with EtOAc, washedwith water, 5 N NaOH, and brine, dried over anhydrous magnesium sulfate,filtered and concentrated to afford 14.4 g (84%) of 3-chloropropoxybenzene as a clear oil.

¹H NMR (DMSO-d6) δ 7.3 (m, 2H), 6.9 (m, 3H), 4.1 (t, 2H, J=6 Hz), 3.6(t, 2H, J=6 Hz), and 2.1 (quintet, 2H, J=6 Hz). IR (CHCl₃, cm⁻¹) 1600,1587, 1498, 1470, 1244, 1226, 1172, and 1039. MS (EI) m/e 170. Anal.Calcd for C₉H₉H₁₁ClO: C, 63.35; H, 6.50; Cl, 20.78. Found C, 65.60; H,6.57; Cl, 17.41.

b) (3-phenoxypropylsulfanyl)-acetic acid methyl ester

A solution of 3-chloropropoxy benzene (1.00 g, 5.86 mmol), thioglycolatemethyl ester (0.622 g, 5.86 mmol) and potassium carbonate (1.00 g, 7.25mmol) in 5 mL of DMF was stirred at room temperature for 48 h, thensonicated at 50–60° C. for 8 h, then stirred at room temperature for anadditional 64 h. The mixture was diluted with EtOAc, washed with waterand brine, dried over anhydrous magnesium sulfate, filtered andconcentrated to afford 1.29 g (92%) of (3-phenoxypropylsulfanyl)-aceticacid methyl ester as a clear oil.

¹H NMR (DMSO-d6) δ 7.3 (m, 2H), 6.9 (m, 3H), 4.0 (t, 2H, J=6 Hz), 3.65(s, 3H), 3.4 (s, 2H), 2.7 (t, 2H, J=7 Hz), and 1.9 (m, 2H). IR (CHCl₃,cm⁻¹) 2954, 1734, 1600, 1587, 1497, 1469, 1437, 1289, and 1244. MS (FD)m/e 241. Anal. Calcd for C₁₂H₁₆O₃S: C, 59.98; H, 6.71. Found C, 58.81;H, 6.24.

c) (3-phenoxypropylsulfanyl)-acetic acid

A solution of (3-phenoxypropylsulfanyl)-acetic acid methyl ester (1.20g, 5.0 mmol) and 1 N NaOH (15.0 mL, 15 mmol) in 15 mL of methanol wasstirred at room temperature for 48 h. The solvent was removed in vacuo,the residue triturated with EtOAc, then dissolved in 1 N HCl and EtOAc.The organic layer was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 0.853 g (75%) of3-phenoxypropylsulfanyl)-acetic acid as a clear oil.

¹H NMR (DMSO-d6) δ 12.5 (br s, 1H), 7.3 (m, 2H), 6.9 (m, 3H), 4.0 (t,2H, J=6 Hz), 3.3 (s, 2H), 2.7 (t, 2H, J=7 Hz), and 2.0 (quintet, 2H, J=6Hz). IR (CHCl₃, cm⁻¹) 3010, 2944, 1711, 1601, 1497, 1301, 1290, 1244,and 1172. MS (ESI) m/e 227, 225. Anal. Calcd for C₁₁H₁₄O₃S: C, 58.38; H,6.23; S, 14.17. Found C, 58.16; H, 6.20; S, 13.78.

d) 4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1b, from 4-(1H-tetrazol-5-yl)-benzoicacid methyl ester (0.714 g, 3.5 mmol) and(3-phenoxypropylsulfanyl)-acetic acid (0.8 g, 3.54 mmol). Purificationby column chromatography on silica gel (elution with linear gradient of15–100% ethyl acetate/hexane) afforded 0.985 g (73%) of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester as a tan solid (W 97–100° C., MW 384.46).

¹H NMR (CDCl₃) δ 8.17 (d, 2H, J=9 Hz), 8.12 (d, 2H, J=9 Hz), 7.26 (t,2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.87 (d, 2H, J=8 Hz), 4.06 (t, 2H,J=6 Hz), 3.97 (s, 31), 3.96 (s, 2H), 2.86 (t, 2H, J=7 Hz), and 2.11 (m,2H). IR (KBr, cm⁻¹) 2920, 1718, 1604, 1439, 1280, 1254, 1109, 755, and709. MS (ES) m/e 385, 383. Anal. Calcd for C₂₀H₂₀N₂O₄S: C, 62.48; H,5.24; N, 7.29; S, 8.34. Found C, 62.90; H, 5.77; N, 7.30; S, 8.81.

e) 4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

A suspension of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester (0.961 g, 2.5 mmol), and lithium hydroxide (0.183 g, 7.5mmol) in 9 mL THF and 4 mL H₂O was stirred at room temperature for 4 h.The THF was removed in vacuo, an additional 10 mL of H₂O was added, andthe heterogeneous aqueous mixture was adjusted to pH 1.8 withconcentrated HCl. The resultant precipitate was collected by filtration,washed with H₂O, and dried in vacuo at 40° C. to afford 0.917 g (99%) of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidas an off-white solid (M 180–185° C., MW 370.43).

¹H NMR (DMSO-d6)

13.30 (bs, 1H), 8.11 (d, 2H, J=9 Hz), 8.07 (d, 2H, J=9 Hz), 7.23 (t, 2H,J=8 Hz), 6.88 (m, 3H), 4.15 (s, 2H), 4.01 (t, 2H, J=6 Hz), 2.78 (t, 2H,J=7 Hz), and 1.99 (m; 2H). IR (KBr, cm⁻¹) 2997, 2643, 2522, 1709, 1471,1267, 1242, 753, and 714. MS (ESI) m/e 371, 369. Anal. Calcd forC₁₉H₁₈N₂O₄S: C, 61.61; H, 4.90; N, 7.56; S, 8.66. Found C, 62.26; H,5.52; N, 7.54; S, 8.29.

f)N-(3-dimethylaminopropyl)-4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

A solution of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.37 g, 1.0 mmol), and 1,1′-carbonyldiimidazole (0.164 g, 1.01 mmol) in10.0 mL THF was stirred at 60° C. for 0.5 h. The reaction solution wasallowed to cool to ambient temperature followed by addition of3-(dimethylamino)propylamine (0.152 mL, 1.2 mmol), then stirred at roomtemperature for 6 h. The THF was concentrated in vacuo, and the oilyresidue redissolved in ethyl acetate/H₂O. The solvent layers wereseparated, and the ethyl acetate layer was washed with H₂O and brine,dried over anhydrous sodium sulfate, filtered, concentrated in vacuo toafford 0.342 g of a tan solid. Purification by column chromatography onsilica gel (isocratic elution with 1:1 toluene/ethyl acetate followed by9:1 CHCl₃/2.0 M ammonia in methanol) afforded 0.256 g (56%) ofN-(3-dimethylaminopropyl)-4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white solid (MP 77–80° C., MW 454.60).

¹H NMR (CDCl₃) δ 8.79 (bs, 1H), 8.12 (d, 2H, J=8 Hz), 8.01 (d, 2H, J=8Hz), 7.26 (t, 2H, J=8 Hz), 6.92 (t, 1H, J=7 Hz), 6.88 (d, 2H, J=8 Hz),4.06 (t, 2H, J=6 Hz), 3.95 (s, 2H), 3.64 (m, 2H), 2.86 (t, 2H, J=7 Hz),2.77 (m, 2H), 2.52 (bs, 6H), 2.11 (m, 2H), and 1.96 (m, 2H). IR (KBr,c⁻¹) 3304, 3063, 2937, 2814, 2762, 1633, 1586, 1561, 1554, 1541, 1499,1469, 1245, 1183, 853, and 751. MS (ESI) m/e 455, 453. Anal. Calcd forC₂₄H₃₀N₄O₃S: C, 63.41; H, 6.65; N, 12.32; S, 7.05. Found C, 63.29; H,6.67; N, 12.34; S, 7.03.

Example 48 Preparation ofN-(3-dimethylaminopropyl)-4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) 4-chlorobutoxy benzene

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47a, from phenol (4.75 g, 50.0 mmol) and1-bromo-4-chlorobutane (5.82 mL, 50.0 mmol) to afford 9.5 g(quantitative) of 4-chlorobutoxy benzene as a colorless oil (MW 184.67).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 4.00 (t, 2H, J=6 Hz), 3.62 (t, 2H, J=6 Hz), and 1.97 (m,4H). IR (CHCl₃, cm⁻¹) 3012, 2960, 2875, 1599, 1587, 1498, 1471, 1244,and 1172. MS (EI) m/e 184. Anal. Calcd for C₁₀H₁₃ClO: C, 65.04; H, 7.10;Cl, 19.20. Found C, 64.96; H, 7.03; Cl, 18.91.

b) (4-phenoxybutylsulfanyl)-acetic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47b, from 4-chlorobutoxybenzene (1.85 g,10.0 mmol) and methyl thioglycolate (1.03 mL, 11.0 mmol) to afford 2.46g (96%) of (4-phenoxybutylsulfanyl)-acetic acid methyl ester as acolorless oil (MW 254.35).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.93 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 3.98 (t, 2H, =6 Hz), 3.73 (s, 3H), 3.24 (s, 2H), 2.72 (t,2H, J=7 Hz), and 1.86 (m, 4H). IR (CHCl₃, cm⁻¹) 3012, 2930, 1733, 1600,1497, 1287, and 1244. MS (FD) m/e 254. Anal. Calcd for C₁₃H₁₈O₃S: C,61.39; H, 7.13; S, 12.61. Found C, 60.43; H, 7.06; S, 10.84.

c) (4-phenoxybutylsulfanyl)-acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47c, from 4-phenoxybutylsulfanyl)-aceticacid methyl ester (2.29 g, 9.0 mmol) and 2NaOH (13.5 mL, 27.0 mmol) toafford 2.04 g (94%) of (4-phenoxybutylsulfanyl)-acetic acid as a paleyellow solid (MP 48–50° C., MW 240.32).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 3.98 (t, 2H, J=6 Hz), 3.28 (s, 2H), 2.74 (t, 2H, J=7 Hz),and 1.86 (m, 4H). IR (CHCl₃, cm⁻¹) 3010, 2944, 1710, 1600, 1497, 1300,1291, 1244, and 1172. MS (ESI) m/e 241, 239. Anal. Calcd for C₁₂H₁₆O₃S:C, 59.97; H, 6.71; S, 13.34. Found C, 58.55; H, 6.66; S, 16.01.

d) 4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47d, from 4-(1H-tetrazol-5-yl)-benzoicacid methyl ester (0.817 g, 4.0 mmol) and(4-phenoxybutylsulfanyl)-acetic acid (0.971 g, 4.04 mmol). Purificationby column chromatography on silica gel (elution with linear gradient of10–100% ethyl acetate/hexane) afforded 1.08 g (68%) of4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester as an off-white solid (MP 98–105° C., MW 398.48).

¹H NMR (CDCl₃) δ 8.17 (d, 2H, J=9 Hz), 8.13 (d, 2H, J=9 Hz), 7.26 (t,2H, J=8 Hz), 6.92 (t, 1H, J=8 Hz), 6.86 (d, 2H, J=8 Hz), 3.96 (m, 7H),2.73 (t, 2H, J=7 Hz), and 1.87 (m, 4H). IR (KBr, cm⁻¹) 2930, 1713, 1554,1498, 1426, 1289, 1283, 1241, 1119, 1112, 754, and 713. MS (ESI) m/e399, 397. Anal. Calcd for C₂₁H₂₂N₂O₄S: C, 63.30; H, 5.56; N, 7.03; S,8.05. Found C, 63.41; H, 6.04; N, 6.82; S, 7.97.

e) 4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47e, from4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester (1.04 g, 2.6 mmol), and lithium hydroxide (0.191 g, 7.8mmol) to afford 1.0 g (quantitative) of4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidas an off-white solid (P 153–160° C., MW 384.46).

¹H NMR (DMSO-d₆)

13.25 (bs, 1H), 8.11 (d, 2H, J=9 Hz), 8.08 (d, 2H, J=9 Hz), 7.22 (t, 2H,J=8 Hz), 6.87 (m, 3H), 4.12 (s, 2H), 3.93 (t, 2H, J=6 Hz), 2.69 (t, 2H,J=7 Hz), and 1.73 (m, 4H). IR (KBr, cm⁻¹) 3314, 2925, 2851, 1705, 1684,1498, 1293, 1247, 748, and 715. MS (ESI) m/e 385, 383. Anal. Calcd forC₂₀H₂₀N₂O₄S: C, 62.48; H, 5.24; N, 7.29; S, 8.34. Found C, 63.19; H,5.99; N, 7.13; S, 8.37.

f)N-(3-dimethylaminopropyl)-4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

A solution of4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.384 g, 1.0 mmol), and 1,1′-carbonyldiimidazole (0.164 g, 1.01 mmol)in 8.0 mL THF was stirred at 65° C. for 0.5 h. The reaction solution wasallowed to cool to ambient temperature followed by addition of3-(dimethylamino)propylamine (0.152 mL, 1.2 mmol), then stirred at roomtemperature for 4.5 h. The TIE was concentrated in vacuo, and the oilyresidue redissolved in 5–10% THF/ethyl acetate and H₂O. The solventlayers were separated, and the ethyl acetate/THF layer was washed withH₂O, saturated aqueous NaHCO₃ solution, and brine, dried over anhydroussodium sulfate, filtered, concentrated in vacuo to afford 0.334 g of atan solid. Crystallization from EtOH/diethyl ether afforded 0.182 g(39%) ofN-(3-dimethylaminopropyl)-4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white solid (MP 87–93° C., MW 468.62).

¹H NMR (CDCl₃) δ 8.75 (bs, 1H), 8.12 (d, 2H, J=8 Hz), 8.03 (d, 2H, J=8Hz), 7.26 (t, 2H, J=8 Hz), 6.92 (t, 1H, J=7 Hz), 6.86 (d, 2H, J=8 Hz),3.96 (t, 2H, J=6 Hz), 3.94 (s, 2H), 3.64 (m, 2H), 2.83 (m, 2H), 2.73 (t,2H, J=7 Hz), 2.56 (bs, 6H), 1.99 (m, 2H), and 1.86 (m, 4H). IR (KBr,cm⁻¹) 3341, 2941, 2764, 1640, 1552, 1536, and 1244. MS (ESI) m/e467,469. Anal. Calcd for C₂₅H₃₂N₄O₃S: C, 64.08; H, 6.88; N, 11.96; S,6.84. Found C, 63.76; H, 6.97; N, 11.56; S, 6.72.

Example 49 Preparation ofdimethyl-(3-{4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

a) 3-chloropropoxy benzene

The above compound was prepared as exemplified in Example 47a.

b) (3-phenoxypropylsulfanyl)-acetic acid methyl ester

The above compound was prepared as exemplified in Example 47b from3-chloropropoxy benzene (3.41 g, 20.0 mmol) and methyl thioglycolate(2.07 mL, 22.0 mmol). Purification by column chromatography on silicagel (isocratic elution with 10% ethyl acetate/toluene) afforded 2.95 g(61%) of (3-phenoxypropylsulfanyl)-acetic acid methyl ester as acolorless oil (MW 240.32).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.93 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 4.06 (t, 2H, J=6 Hz), 3.73 (s, 3H), 3.25 (s, 2H), 2.84 (t,2H, J=7 Hz), and 2.08 (m, 2H). IR (CHCl₃, cm⁻¹) 3010, 2954, 1734, 1601,1497, 1437, 1288, 1244, and 1225. MS (ES) m/e 241. Anal. Calcd forC₁₂H₁₆O₃S: C, 59.97; H, 6.71; S, 13.34. Found C, 59.22; H, 6.71; S,18.00.

c) (3-phenoxypropylsulfanyl)-acetic acid

The above compound was prepared as exemplified in Example 47c from(3-phenoxypropylsulfanyl)-acetic acid methyl ester (2.64 g, 11.0 mmol)and 2N NaOH (16.5 mL, 33.0 mmol) to afford 2.33 g (94%) of(3-phenoxypropylsulfanyl)-acetic acid as a white crystalline solid (O35–37° C., MW 226.30).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 4.06 (t, 2H, J=6 Hz), 3.28 (s, 2H), 2.87 (t, 2H, J=7 Hz),and 2.11 (m, 2H). IR (CHCl₃, cm⁻¹) 3041, 2927, 2674, 2565, 1710, 1601,1498, 1244, 1172 and 1040. MS (ESI) m/e 227, 225. Anal. Calcd forC₁₁H₁₄O₃S: C, 58.38; H, 6.24; S, 14.17. Found C, 57.95; H, 6.08; S,14.11.

d) 4-hydroxy-benzoic acidN′-[2-(3-phenoxypropylsulfanyl)-acetyl]-hydrazide

A solution of (3-phenoxypropylsulfanyl)-acetic acid (1.13 g, 5.0 mmol),and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (1.25 g, 5.0mmol) in 5.0 mL THF and 20.0 mL acetonitrile was stirred at ambienttemperature for 1.0 h followed by addition of 4-hydroxybenzoic hydrazide(0.776 g, 5.0 mmol), then stirred at room temperature for 66 h. TheTHF/acetonitrile were concentrated in vacuo and the resultant off-whitesolid redissolved in 20% THF/ethyl acetate. The ethyl acetate/THFsolution was washed with 1N HCl, H₂O, saturated aqueous NaHCO₃ solution,and brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford an off-white solid. The solid wastriturated with a mixture of CH₂Cl₂/diethyl ether/n-hexane, filtered,and the collected solid washed with diethyl ether and n-hexane to afford1.53 g (85%) of 4-hydroxy-benzoic acidN′-[2-(3-phenoxypropylsulfanyl)-acetyl]-hydrazide as an amorphous whitesolid (MP 146–151° C., MW 360.44).

¹H NMR (DMSO-d₆) δ 10.14 (s, 1H), 10.07 (s, 1H), 9.96 (s, 1H), 7.73 (d,2H, J=9 Hz), 7.26 (t, 2H, J=8 Hz), 6.91 (m, 3H), 6.79 (d, 2H, J=8 Hz),4.02 (t, 2H, J=6 Hz), 3.22 (s, 2H), 2.78 (t, 2H, J=7 Hz), and 2.00 (m,2H). IR (KBr, cm⁻¹) 3304, 3228, 1667, 1607, 1575, 1514, 1498, 1468,1277, 1250, 1235, and 755. MS (ESI) m/e 361, 359. Anal. Calcd forC₁₈H₂₀N₂O₄S: C, 59.98; H, 5.59; N, 7.77; S, 8.90. Found C, 59.94; H,5.62; N, 7.73; S, 8.92.

e) 4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol

A heterogeneous mixture of 4-hydroxy-benzoic acidN′-[2-(3-phenoxypropylsulfanyl)-acetyl]-hydrazide (1.44 g, 4.0 mmol),triphenylphosphine (2.12 g, 8.0 mmol), triethylamine (2.0 mL, 14.4 mmol)and carbon tetrachloride (1.61 mL, 16.5 mmol) in 20 mL acetonitrile wasstirred at room temperature for 2.5 h. The resultant precipitate wascollected by filtration, washed with acetonitrile and discarded. Thefiltrate was concentrated in vacuo and the resultant solid redissolvedin 10% THF/ethyl acetate.

The ethyl acetate/THF solution was washed with 1N HCl, H₂O, saturatedaqueous NaHCO₃ solution, and brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to afford 3.92 g of ayellow oil. Purification by column chromatography on silica gel (elutionwith linear gradient of 0–100% ethyl acetate/toluene) afforded 1.15 g(83%) of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol as awhite solid (MP 122–127° C., MW 342.42).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=9 Hz), 7.26 (t, 2H, J=8 Hz), 6.96 (d,2H, J=9 Hz), 6.93 (t, 1H, J=8 Hz), 6.87 (d, 2H, J=8 Hz), 4.05 (t, 2H,J=6 Hz), 3.92 (s, 2H), 2.85 (t, 2H, J=7 Hz), and 2.10 (m, 2H). IR (KBr,cm⁻¹) 3442, 3127, 2944, 1609, 1599, 1586, 1497, 1472, 1246, 1229, 1174,and 756. MS (ESI) m/e 343, 341. Anal. Calcd for C₁₈H₁₈N₂O₃S: C, 63.14;H, 5.30; N, 8.18; S, 9.36. Found C, 63.31; H, 5.32; N, 8.14; S, 9.17.

f)Dimethyl-(3-{4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

A heterogeneous mixture of4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.342 g, 1.0 mmol), 3-chloro-N,N-dimethylpropylamine hydrochloride(0.174 g, 1.1 mmol), and sodium hydride (0.092 g, 2.3 mmol) in 10 mL DMFwas stirred at 100° C. for 2.5 h. The reaction mixture was allowed tocool to room temperature and diluted with ethyl acetate/H₂O. The solventlayers were separated, the aqueous layer back extracted with ethylacetate, the combined organic extracts washed with water and brine,dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto afford 0.332 g of a yellow oil. Purification by column chromatographyon silica gel (isocratic elution with 1:1 toluene/ethyl acetate followedby 9:1 CHCl₃/2.0 M ammonia in methanol) afforded 0.188 g (44%) ofdimethyl-(3-{4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas an oily gum. The gum (0.182 g, 0.426 mmol) was dissolved in 2 mLacetone, and oxalic acid (0.042 g, 0.468 mmol), dissolved in 1 mLacetone, was added with rapid stirring at room temperature. Filtered theresultant thick precipitate, washed the collected solid with acetone anddiethyl ether, and dried in vacuo at 40° C. to afford 0.205 g (93%) ofdimethyl-(3-{4-[5-(3-phenoxypropylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt as a white solid (MP 131–133° C., MW oxalate salt517.61, MW free amine 427.57).

¹H NMR (DMSO-d₆) δ 7.91 (d, 2H, J=9 Hz), 7.24 (t, 2H, J=8 Hz), 7.12 (d,2H, J=9 Hz), 6.89 (m, 3H), 4.12 (t, 2H, J=6 Hz), 4.09 (s, 2H), 4.01 (t,2H, J=6 Hz), 3.13 (m, 2H), 2.76 (t, 2H, J=7 Hz), 2.74 (s, 6H), 2.10 (m,2H), and 1.99 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3042, 2928, 1723, 1611,1499, 1472, 1259, 1248, 1177, 756, and 696. MS (ES) m/e 428. Anal. Calcdfor C₂₃H₂₉N₃O₃S.C₂H₂O₄: C, 58.01; H, 6.04; N, 8.12; S, 6.19. Found C,57.72; H, 6.01; N, 7.78; S, 6.55.

Example 50 Preparation ofdimethyl-(3-{4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

a) 4-chlorobutoxy benzene

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47a, from phenol (4.75 g, 50.0 mmol) and1-bromo-4-chlorobutane (5.82 mL, 50.0 mmol) to afford 9.5 g(quantitative) of 4-chlorobutoxy benzene as a colorless oil (MW 184.67).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 4.00 (t, 2H, J=6 Hz), 3.62 (t, 2H, J=6 Hz), and 1.97 (m,4H). IR (CHCl₃, cm⁻¹) 3012, 2960, 2875, 1599, 1587, 1498, 1471, 1244,and 1172. MS (EI) m/e 184. Anal. Calcd for C₁₀H₁₃ClO: C, 65.04; H, 7.10;Cl, 19.20. Found C, 64.96; H, 7.03; Cl, 18.91.

b) (4-phenoxybutylsulfanyl)-acetic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47b, from 4-chlorobutoxy benzene (1.85 g,10.0 mmol) and methyl thioglycolate (1.03 mL, 11.0 mmol) to afford 2.46g (96%) of (4-phenoxybutylsulfanyl)-acetic acid methyl ester as acolorless oil (MW 254.35).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.93 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 3.98 (t, 2H, J=6 Hz), 3.73 (s, 3H), 3.24 (s, 2H), 2.72. (t,2H, J=7 Hz), and 1.86 (m, 4H). IR (CHCl₃, cm⁻¹) 3012, 2930, 1733, 1600,1497, 1287, and 1244. MS (FD) m/e 254. Anal. Calcd for C₁₃H₁₈O₃S: C,61.39; H, 7.13; S, 12.61. Found C, 60.43; H, 7.06; S, 10.84.

c) (4-phenoxybutylsulfanyl)-acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47c, from 4-phenoxybutylsulfanyl)-aceticacid methyl ester (2.29 g, 9.0 mmol) and 2N NaOH (13.5 mL, 27.0 mmol) toafford 2.04 g (94%) of (4-phenoxybutylsulfanyl)-acetic acid as a paleyellow solid (MP 48–50° C., MW 240.32).

¹H NMR (CDCl₃) δ 7.28 (t, 2H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 6.89 (d,2H, J=8 Hz), 3.98 (t, 2H, J=6 Hz), 3.28 (s, 2H), 2.74 (t, 2H, J=7 Hz),and 1.86 (m, 4H). IR (CHCl₃, cm⁻¹) 3010, 2944, 1710, 1600, 1497, 1300,1291, 1244, and 1172. MS (ESI) m/e 241, 239. Anal. Calcd for C₁₂H₁₆O₃S:C, 59.97; H, 6.71; S, 13.34. Found C, 58.55; H, 6.66; S, 16.01.

d) 4-hydroxy-benzoic acidN′-[2-(4-phenoxybutylsulfanyl)-acetyl]-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49d, from (4-phenoxybutylsulfanyl)-aceticacid (0.961 g, 4.0 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(EEDQ) (0.999 g, 4.0 mmol), and 4-hydroxybenzoic hydrazide (0.621 g, 4.0mmol) to afford 1.14 g (76%) of 4-hydroxy-benzoic acidN′-[2-(4-phenoxybutylsulfanyl)-acetyl]-hydrazide as an amorphous whitesolid (MP 113–115° C., MW 374.46).

¹H NMR(DMSO-d₆) δ 10.13 (s, 1H), 10.07 (s, 1H), 9.94 (s, 1H), 7.73 (d,2H, J=9 Hz), 7.25 (t, 2H, J=8 Hz), 6.89 (m, 3H), 6.79 (d, 2H, J=8 Hz),3.96 (t, 2H, J=6 Hz), 3.19 (s, 2H), 2.70 (t, 2H, J=7 Hz), and 1.74 (m,4H). IR (CHCl₃, cm⁻¹) 3281, 3003, 2940, 1631, 1609, 1587, 1497, 1470,1387, 1279, 1244, and 1171. MS (ESI) m/e 375, 373. Anal. Calcd forC₁₉H₂₂N₂O₄S: C, 60.94; H, 5.92; N, 7.48; S, 8.56. Found C, 60.24; H,5.92; N, 7.50; S, 9.12.

e) 4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, using 4-hydroxybenzoic acidN′-[2-(4-phenoxybutylsulfanyl)-acetyl]-hydrazide (1.09 g, 2.9 mmol),triphenylphosphine (1.54 g, 5.8 mmol), and triethylamine (1.46 mL, 10.44mmol) to afford 0.831 g (80%) of4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol as awhite solid (MP 129–130° C., MW 356.45).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=9 Hz), 7.26 (t, 2H, J=8 Hz), 6.95 (d,2H, J=9 Hz), 6.93 (t, 1H, J=8 Hz), 6.86 (d, 2H, J=8 Hz), 3.96 (t, 2H,J=6 Hz), 3.91 (s, 2H), 2.71 (t, 2H, J=7 Hz), and 1.85 (m, 4H—). IR (KBr,cm⁻¹) 3096, 2935, 1610, 1600, 1567, 1498, 1475, 1456, 1284, 1275, 1237,1178, 757, and 691. MS (ESI) m/e 357, 355. Anal. Calcd for C₁₉H₂₀N₂O₃S:C, 64.02; H, 5.66; N, 7.86; S, 9.00. Found C, 63.81; H, 5.68; N, 7.84;S, 9.09.

f)[Dimethyl-(3-{4-[5-(4-phenoxybutylsulfanylmethyl)-1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

A heterogeneous mixture of 4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.178 g, 0.5 mmol),3-chloro-N,N-dimethylpropylamine hydrochloride (0.087 g, 0.55 mmol), andsodium hydride (0.046 g, 1.15 mmol) in 5 mL DMF was stirred at 100° C.for 2.5 h. The reaction mixture was allowed to cool to room temperatureand diluted with ethyl acetate/H₂O. The solvent layers were separated,the aqueous layer back extracted with ethyl acetate, the combinedorganic extracts washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to afford 0.223 g ofa tan solid. Purification by column chromatography on silica get(isocratic elution with 1:1 toluene/ethyl acetate followed by 9:1CHCl₃/2.0M ammonia in methanol) afforded 0.15 g (68%) ofdimethyl-(3-{4-[5-(4-phenoxybutylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy})-propyl)-amineas a white solid (MP 69–73° C., MW 441.60).

¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=9 Hz), 7.26 (t, 2H, J=8 Hz), 6.97 (d,2H, J=9 Hz), 6.92 (t, 1H, J=7 Hz), 6.87 (d, 2H, J=8 Hz) 4.13 (t, 2H, J=6Hz), 3.96 (t, 2H, J=6 Hz), 3.91 (s, 2H), 2.92 (m, 2H), 2.72 (t, 2H, J=7Hz), 2.60 (1's, 6H), 2.25 (m, 2H), and 1.84 (m, 4H). IR (KBr, cm⁻¹)2947, 1612, 1501, 1468, 1258, and 749. MS (ESI) m/e 442, 440. Anal.Calcd for C₂₄H₃₁N₃O₃S: C, 65.28; H, 7.08; N, 9.52; S, 7.26. Found C,65.36; H, 7.12; N, 9.38; S, 7.39.

Example 51 Preparation ofdimethyl-(3-{4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

a) 4-hydroxybenzoic acid N′-(6-phenylhexanoyl)-hydrazide

A solution of 6-phenylhexanoic acid (0.961 g, 5.0 mmol), and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (1.25 g, 5.0 mmol)in 5.0 mL THF and 20.0 ml acetonitrile was stirred at ambienttemperature for 1.0 h followed by addition of 4-hydroxy-benzoichydrazide (0.776 g, 5.0 mmol), then stirred at room temperature for 18 hfollowed by heating at 65° C. for 1.5 h. The reaction mixture wasallowed to cool to room temperature, the THF/acetonitrile wereconcentrated in vacuo, and the resultant gold oil redissolved in ethylacetate. The ethyl acetate solution was washed with 1N HCl, H₂O,saturated aqueous NaHCO₃ solution, and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford anoff-white solid. The solid was triturated with a mixture ofCH₂Cl₂/diethyl ether/n-hexane, filtered, and the collected solid washedwith diethyl ether and n-hexane to afford 1.16 g (71%) of4-hydroxy-benzoic acid N′-(6-phenylhexanoyl)-hydrazide as an amorphouswhite solid (MP 155–160° C., MW 326.40).

¹H NMR (DMSO-d₆) δ 10.04 (s, 1H), 9.98 (s, 1H), 9.69 (s, 1H), 7.72 (d,2H, J=9 Hz), 7.25 (t, 2H, J=8 Hz), 7.16 (m, 3H), 6.79 (d, 2H, J=8 Hz),2.55 (t, 2H, J=8 Hz), 2.14 (t, 2H, J=7 Hz), 1.56 (m, 4H) and 1.32 (m,2H). IR (KBr, cm⁻¹) 3314, 3222, 3023, 2930, 2856, 1699, 1626, 1609,1584, 1517, 1492, 1287, 1237, and 697. MS (ESI) m/e 327, 325. Anal.Calcd for C₁₉H₂₂N₂O₃: C, 69.92; H, 6.79; N, 8.58. Found C, 69.83; H,6.66; N, 8.43.

b) 4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-hydroxy-benzoic acidN′-(6-phenylhexanoyl)-hydrazide (1.1 g, 3.4 mmol), triphenylphosphine(1.8 g, 6.8 mmol), and triethylamine (1.71 mL, 12.24 mmol) to afford0.841 g (80%) of 4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenol asa white solid (MP 118–123° C., MW 308.38).

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=9 Hz), 7.27 (t, 2H, J=8 Hz), 7.17 (m,3H), 6.98 (d, 2H, J=8 Hz), 2.91 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=8 Hz),1.86 (m, 2H), 1.68 (m, 2H), and 1.48 (m, 2H). IR (KBr, cm⁻¹) 2921, 1610,1600, 1496, 1283, and 1231. MS (ESI) m/e 309, 307. Anal. Calcd forC₁₉H₂₀N₂O₂: C, 74.00; H, 6.54; N, 9.08. Found C, 73.52; H, 6.40; N,8.66.

c)Dimethyl-(3-{4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, from4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.154 g, 0.5 mmol)to afford 0.119 g (60%) ofdimethyl-(3-{4-[5-(5-phenylpentyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas a white solid (NV 49–50° C., MW 393.53).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=9 Hz), 7.27 (t, 2H, J=7 Hz), 7.18 (m,3H), 6.98 (d, 2H, J=9 Hz), 4.13 (t, 2H, J=6 Hz), 2.91 (t, 2H, J=7 Hz),2.88 (m, 2H), 2.63 (t, 2H, J=8 Hz), 2.56 (bs, 6H), 2.23 (m, 2H), 1.87(m, 2H), 1.68 (m, 2H), and 1.49 (m, 2H). IR (KBr, cm⁻¹) 3083, 3026,2938, 2859, 2764, 1612, 1574, 1502, 1466, 1259, 1176, and 999. MS (ESI)m/e 394, 392. Anal. Calcd for C₂₄H₃₁N₃O₂: C, 73.25; H, 7.94; N, 10.68.Found C, 72.94; H, 7.99; N, 10.52.

Example 52 Preparation ofdimethyl-(3-{4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

a) 4-hydroxy-benzoic acid N′-(7-phenylheptanoyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 7-phenylheptanoic acid (1.06 g,5.0 mmol) to afford 1.39 g (81%) of 4-hydroxy-benzoic acidN′-(7-phenylheptanoyl)-hydrazide as a white solid (154–158° C., MW340.43).

¹H NMR (DMSO-d₆) δ 10.04 (s, 1H), 9.97 (s, 1H), 9.68 (s, 1H), 7.72 (d,2H, J=9 Hz), 7.25 (t, 2H, J=7 Hz), 7.15 (m, 3H), 6.79 (d, 2H, J=9 Hz),2.55 (t, 2H, J=8 Hz), 2.13 (t, 2H, J=8 Hz), 1.53 (m, 4H) and 1.29 (m,4H). IR (KBr, cm⁻¹) 3213, 3024, 2931, 2855, 1765, 1684, 1670, 1646,1610, 1583, 1506, 1492, 1464, 1453, 1308, 1279, 1254, 1225, 1174, and699. MS (ES) m/e 341, 339. Anal. Calcd for C₂₀H₂₄N₂O₃: C, 70.57; H,7.11; N, 8.23. Found C, 69.87; H, 7.05; N, 8.00.

b) 4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-hydroxy-benzoic acidN′-(7-phenylheptanoyl)-hydrazide (1.3 g, 3.82 mmol), triphenylphosphine(2.02 g, 7.64 mmol), and triethylamine (1.92 mL, 13.75 mmol) to afford0.883 g (71%) of 4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenol as awhite solid (MP 125–129° C., MW 322.41).

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=9 Hz), 7.27 (t, 2H, J=8 Hz), 7.17 (m,3H), 6.98 (d, 2H, J=8 Hz), 2.90 (t, 2H, J=7 Hz), 2.60 (t, 2H, J=8 Hz),1.84 (m, 2H), 1.64 (m, 2H), and 1.43 (m, 4H). IR (KBr, cm⁻¹) 3061, 3020,2925, 2852, 2809, 2686, 2608, 2481, 1612, 1600, 1577, 1498, 1466, 1375,1286, 1239, and 1174. MS (ESI) m/e 323, 321. Anal. Calcd for C₂₀H₂₂N₂O₂:C, 74.51; H, 6.88; N, 8.69. Found C, 74.27; H, 6.76; N, 8.61.

c)Dimethyl-(3-{4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, from4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.161 g, 0.5 mmol)to afford 0.153 g (75%) ofdimethyl-(3-{4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas an oily gum. The gum (0.151 g, 0.37 mmol) was dissolved in 2 mLacetone, and oxalic acid (0.037 g, 0.41 mmol), dissolved in 1 mLacetone, was added with rapid stirring at room temperature. Filtered theresultant thick precipitate, washed the collected solid with acetone anddiethyl ether, and dried in vacuo at 40° C. to afford 0.18 g (97%) ofdimethyl-(3-{4-[5-(6-phenylhexyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt as a white solid (M 147–152° C., MW oxalate salt497.60, MW free amine 407.56).

¹H NMR (DMSO-d₆) δ 7.90 (d, 2H, J=9 Hz), 7.24 (t, 2H, J=7 Hz), 7.15 (m,3H), 7.11 (d, 2H, J=9 Hz), 4.12 (t, 2H, J=6 Hz), 3.13 (t, 2H, J=7 Hz),2.87 (t, 2H, J=7 Hz), 2.74 (s, 6H), 2.54 (t, 2H, J=8 Hz), 2.08 (m, 2H),1.72 (m, 2H), 1.55 (m, 2H), and 1.34 (m, 4H). IR (KBr, cm⁻¹) 2970, 2925,2854, 2676, 1721, 1612, 1590, 1496, 1311, 1232, 1177, 1040, and 842. MS(ESI) m/e 408, 408.5. Anal. Calcd for C₂₅H₃₃N₃O₂.C₂H₂O₄: C, 65.17; H,7.09; N, 8.44. Found C, 64.95; H, 6.94; N, 8.39.

Example 53 Preparation ofdimethyl-(3-{4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

a) 4-hydroxy-benzoic acid N′-(8-phenyloctanoyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51aa, from 8-phenyloctanoic acid (1.14 g,5.0 mmol) to afford 1.27 g (71%) of 4-hydroxy-benzoic acidN′-(8-phenyloctanoyl)-hydrazide as a white solid (MP 150–152° C., MW354.45).

¹H NMR (DMSO-d₆) δ 10.04 (s, 1H), 9.97 (s, 1H), 9.68 (s, 1H), 7.72 (d,2H, J=9 Hz), 7.24 (t, 2H, J=7 Hz), 7.15 (m, 3H), 6.79 (d, 2H, J=9 Hz),2.55 (t, 2H, J=8 Hz), 2.13 (t, 2H, J=8 Hz), 1.53 (m, 4H) and 1.28 (bs,6H). IR (KBr, cm⁻¹) 3280, 3023, 2927, 2852, 1759, 1659, 1607, 1575,1515, 1494, 1277, 1237, 1181, 845, and 698. MS (ESI) m/e 355, 353. Anal.Calcd for C₂₁H₂₆N₂O₃: C, 71.16; H, 7.39; N, 7.90. Found C, 70.45; H,7.34; N, 7.69.

b) 4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-hydroxy-benzoic acidN′-(8-phenyloctanoyl)-hydrazide (1.2 g, 3.4 mmol), triphenylphosphine(1.8 g, 6.8 mmol), and triethylamine (1.71 mL, 12.24 mmol) to afford0.935 g (82%) of 4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenol asa white solid (MP 138–140° C., MW 336.44).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=9 Hz), 7.27 (t, 2H, J=8 Hz), 7.17 (m,3H), 6.99 (d, 2H, J=9 Hz), 2.90 (t, 2H, J=8 Hz), 2.59 (t, 2H, J=8 Hz),1.82 (m, 2H), 1.61 (m, 2H), and 1.37 (m, 6H). IR (KBr, cm⁻¹) 3083, 3063,3024, 2925, 2852, 1611, 1599, 1576, 1497, 1467, 1454, 1287, 1234, 1174,862, 819, 739, and 695. MS (ESI) m/e 337, 335. Anal. Calcd forC₂₁H₂₄N₂O₂: C, 74.97; H, 7.19; N, 8.33. Found C, 74.90; H, 7.05; N,8.36.

c)Dimethyl-(3-{4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, using4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.168 g, 0.5 mmol)to afford 0.198 g (94%) ofdimethyl-(3-{4-[5-(7-phenylheptyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas an off-white solid (AD 36–39° C., MW 421.59).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=9 Hz), 7.27 (t, 2H, J=7 Hz), 7.17 (m,3H), 6.98 (d, 2H, J=9 Hz), 4.12 (t, 2H, J=6 Hz), 2.89 (t, 2H, J=8 Hz),2.74 (m, 2H, 2.59 (t, 2H, J=8 Hz), 2.48 (bs, 6H), 2.16 (m, 2H), 1.81 (m,2H), 1.62 (m, 2H), and 1.37 (m, 6H). IR (KBr, cm⁻¹) 2925, 2853, 2765,1613, 1500, 1468, 1254, 1174, and 836. MS (ESI) m/e 420, 422. Anal.Calcd for C₂₆H₃₅N₃O₂: C, 74.07; H, 8.37; N, 9.97. Found C, 73.88; H,8.44; N, 9.90.

Example 54 Preparation ofN-(2-dimethylaminoethyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47f, from4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.178 g, 0.5 mmol), 1,1′-carbonyldiimidazole (0.082 g, 0.505 mmol), and2-(dimethylamino)ethylamine (0.069 mL, 0.6 mmol) to afford 0.128 g (60%)ofN-(2-dimethylaminoethyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas a white solid (MP 94–100° C., MW 426.54).

¹H NMR (CDCl₃) δ 8.15 (t, 1H, J=7 Hz), 8.12 (s, 4H), 7.27 (t, 2H, J=8Hz), 6.95 (t, 1H, J=7 Hz), 6.89 (d, 2H, J=8 Hz), 4.22 (t, 2H, J=6 Hz),4.08 (s, 2H), 3.79 (m, 2H), 3.07 (t, 2H, J=6 Hz), 2.99 (m, 2H), and 2.67(bs, 6H). IR (KBr, cm⁻¹) 3350, 2943, 2819, 2766, 1643, 1554, 1538, 1494,1245, 1033, 863, and 750. MS (ESI) m/e 427, 425. Anal. Calcd forC₂₂H₂₆N₄O₃S: C, 61.95; H, 6.14; N, 13.14; S, 7.52. Found C, 61.40; H,5.90; N, 13.00; S, 7.59. Analytical HPLC: 97% purity.

Example 55 Preparation ofN-(4-dimethylaminobutyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47f, from4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.178 g, 0.5 mmol), 1,1′-carbonyldiimidazole (0.082 g, 0.505 mmol), and4-(dimethylamino)butylamine (0.07 g, 0.6 mmol) to afford 0.136 g (60%)ofN-(4-dimethylaminobutyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white waxy solid (MP 71–78° C., MW 454.60).

¹H NMR (CDCl₃) δ 8.11 (bs, 1H), 8.09 (d, 2H, J=9 Hz), 8.05 (d, 2H, J=9Hz), 7.27 (t, 2H, J=8 Hz), 6.95 (t, 1H, J=7 Hz), 6.89 (d, 2H, J=8 Hz),4.22 (t, 2H, J=6 Hz), 4.07 (s, 2H), 3.53 (m, 2H), 3.06 (t, 2H, J=6 Hz),2.78 (m, 2H), 2.56 (bs, 6H), and 1.83 (m, 4H). IR (KBr, cm⁻¹) 3338,2943, 1643, 1602, 1554, 1533, 1494, 1468, 1289, 1246, 749, and 691. MS(ESI) m/e 453, 455. Anal. Calcd for C₂₄H₃₀N₄O₃S: C, 63.41; H, 6.65; N,12.32; S, 7.05. Found C, 62.75; H, 6.77; N, 12.53; S, 6.93. AnalyticalHPLC: 97% purity.

Example 56 Preparation ofN-(5-dimethylaminopentyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47f, from4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.178 g, 0.5 mmol), 1,1′-carbonyldiimidazole (0.082 g, 0.505 mmol), and5-(dimethylamino)pentylamine (0.078 g, 0.6 mmol) to afford 0.126 g (53%)ofN-(5-dimethylaminopentyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white waxy solid (MP 83–89° C., MW 468.62).

¹H NMR (CDCl₃) δ 8.11 (bs, 1H), 8.09 (d, 2H, J=8 Hz), 7.98 (d, 2H, J=8Hz), 7.27 (m, 2H), 6.93 (t, 1H, J=7 Hz), 6.89 (d, 2H, J=8 Hz), 4.22 (t,2H, J=6 Hz), 4.07 (s, 2H), 3.52 (m, 2H), 3.06 (t, 2H, J=6 Hz), 2.62 (m,2H), 2.48 (bs, 6H), 1.71 (m, 4H), and 1.54 (m, 2H). IR (KBr, cm⁻¹) 3346,2942, 2761, 1717, 1644, 1554, 1533, and 1246. MS (ES) m/e 467, 469.Anal. Calcd for C₂₅H₃₂N₄O₃S: C, 64.08; H, 6.88; N, 11.96; S, 6.84. FoundC, 63.05; H, 6.78; N, 11.71; S, 6.47. Analytical HPLC: 96% purity.

Example 57 Preparation ofN-(6-dimethylaminohexyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 47f, from4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.178 g, 0.5 mmol), 1,1′-carbonyldiimidazole (0.082 g, 0.505 mmol), and6-(dimethylamino)hexylamine (0.087 g, 0.6 mmol) to afford 0.148 g (61%)ofN-(6-dimethylaminohexyl)-4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamideas an off-white solid (MP 86–93° C., MW 482.65).

¹H NMR (CDCl₃) δ 8.13 (bs, 1H), 8.10 (d, 2H, J=9 Hz), 8.02 (d, 2H, J=9Hz), 7.27 (t, 2H, J=8 Hz), 6.95 (t, 1H, J=8 Hz), 6.89 (d, 2H, J=8 Hz),4.22 (t, 2H, J=6 Hz), 4.07 (s, 2H), 3.51 (m, 2H), 3.06 (t, 2H, J=6 Hz),2.87 (m, 2H), 2.70 (bs, 6H), 1.83 (m, 2H), 1.71 (m, 2H) and 1.47 (m,4H). R (KBr, cm⁻¹) 3339, 2929, 2854, 2815, 2776, 1642, 1602, 1580, 1554,1532, 1492, 1468, 1247, 1017, 749, and 691. MS (ESI) m/e 481, 483. Anal.Calcd for C₂₆H₃₄N₄O₃S: C, 64.70; H, 7.10; N, 11.61; S, 6.64. Found C,63.86; H, 7.13; N, 12.19; S, 6.76. Analytical HPLC: 97% purity.

Example 58 Preparation of{3-[4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethylamine

a) 4-hydroxy-benzoic acid N′-(biphenyl-4-carbonyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 4-biphenylcarboxylic acid (1.04g, 5.0 mmol) to afford 1.52 g (91%) of 4-hydroxy-benzoic acidN′-(biphenyl-4-carbonyl)-hydrazide as an off-white solid (279–281° C.,MW 332.36).

¹H NMR (DMSO-d6) δ 10.44 (s, 1H), 10.24 (s, 1H), 10.09 (s, 1H), 8.00 (d,2H, J=9 Hz), 7.81 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=9 Hz), 7.74 (d, 2H,J=8 Hz), 7.49 (t, 2H, J=8 Hz), 7.40 (t, 1H, J=7 Hz), and 6.84 (d, 2H,J=9 Hz). IR (KBr, cm⁻¹) 3272, 1674, 1622, 1608, 1582, 1513, 1492, 1484,1284, 1277, 1236, 847, and 745. MS (ESI) m/e 331, 333. Anal. Calcd forC₂₀H₁₆N₂O₃: C, 72.28; H, 4.85; N, 8.43. Found C, 72.52; H, 4.99; N,8.27.

b) 4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-hydroxy-benzoic acidN′-(biphenyl-4-carbonyl)-hydrazide (1.33 g, 4.0 mmol),triphenylphosphine (2.12 g, 8.0 mmol), and triethylamine (2.0 mL, 14.4mmol) to afford 0.343 g (27%) of4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenol as an off-white solid(UT 256–260° C., MW 314.35).

¹H NMR (DMSO-d₆) δ 10.34 (s, 1H), 8.17 (d, 2H, J=8 Hz), 7.97 (d, 2H, J=8Hz), 7.92 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz), 7.51 (t, 2H, J=8 Hz),7.42 (t, 1H, J=8 Hz), and 6.97 (d, 2H, J=8 Hz). IR (KBr, cm⁻¹) 3110,1613, 1498, 1483, 1293, 1176, 1074, 838, and 739. MS (ESI) m/e 313, 315.Anal. Calcd for C₂₀H₁₄N₂O₂: C, 76.42; H, 4.49; N, 8.91. Found C, 76.34;H, 4.75; N, 8.35.

c){3-[4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, from4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenol (0.157 g, 0.5 mmol) toafford 0.162 g (81%) of{3-[4-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethylamineas a white solid (MP 130–132° C., MW 399.50).

¹H NMR (CDCl₃)

8.19 (d, 2H, J=9 Hz), 8.09 (d, 2H, J=9 Hz), 7.76 (d, 2H, J=9 Hz), 7.66(d, 2H, J=8 Hz), 7.49 (t, 2H, J=7 Hz), 7.41 (t, 1H, J=7 Hz), 7.03 (d,2H, J=8 Hz), 4.18 (t, 2H, J=6 Hz), 3.07 (m, 2H), 2.72 (bs, 6H), and 2.36(m, 2H). IR (KBr, cm⁻¹) 2940, 2752, 1613, 1473, 1464, 1257, 1006, 842,and 740. MS (ESI) m/e 400. Anal. Calcd for C₂₅H₂₅N₃O₂: C, 75.16; H,6.31; N, 10.52. Found C, 73.89; H, 6.33; N, 10.35. Analytical HPLC: 95%purity.

Example 59 Preparation ofDimethyl-(3-{4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenoxy}-propyl)-amine

a) 4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenol

A heterogeneous mixture of 4-hydroxy-benzoic acidN′-[2-(2-phenoxyethylsulfanyl)-acetyl]-hydrazide (1.04 g, 3.0 mmol), and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's Reagent) (1.25 g, 3.0 mmol) in 30 mL toluene was stirred atreflux temperature (111° C.) for 1.5 h. The reaction mixture was allowedto cool to room temperature and concentrated in vacuo to afford 2.37 gof a yellow solid. Purification by column chromatography on silica gel(elution with linear gradient of 0–100% ethyl acetate/hexane followed byisocratic elution with 5% methanol/ethyl acetate) afforded 0.144 g (14%)of 4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenol asa white solid (MP 127–128° C., MW 344.416).

¹H NMR (DMSO-d₆) δ 10.17 (s, 1H), 7.76 (d, 2H, J=9 Hz), 7.25 (t, 2H, J=8Hz), 6.90 (m, 5H), 4.32 (s, 2H), 4.14 (t, 2H, J=6 Hz), and 2.93 (t, 2H,J=6 Hz). IR (KBr, cm⁻¹) 3415, 3125, 2920, 1600, 1586, 1496, 1243, 1177,1032, 754, and 690. MS (ESI) m/e 345, 343. Anal. Calcd for C₁₇H₁₆N₂O₂S₂:C, 59.28; H, 4.68; N, 8.13; S, 18.62. Found C, 59.24; H, 4.71; N, 8.20;S, 18.36.

b)Dimethyl-(3-{4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared as exemplified in Example 50f, using4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenol (0.12g, 0.35 mmol) to afford 0.038 g (25%) ofdimethyl-(3-{4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-phenoxy}-propyl)-amineas a white solid (MP 72–73° C., MW 429.61).

¹H NMR (CDCl₃) δ 7.87 (d, 2H, J=9 Hz), 7.26 (t, 2H, J=8 Hz), 6.95 (d,2H, J=9 Hz), 6.91 (t, 1H, J=8 Hz), 6.88 (d, 2H, J=8 Hz), 4.22 (s, 2H),4.18 (m, 4H), 3.25 (m, 2H), 2.99 (t, 2H, J=6 Hz), 2.87 (s, 3H), 2.86 (s,3H), and 2.47 (m, 2H). IR (KBr, cm⁻¹) 2948, 2923, 2873, 2825, 2779,1602, 1499, 1465, 1452, 1253, 1178, 1057, 955, 842, and 757. MS (ESI)m/e 428, 430. Anal. Calcd for C₂₂H₂₇N₃O₂S₂: C, 61.51; H, 6.33; N, 9.78;S, 14.93. Found C, 61.89; H, 6.68; N, 9.19; S, 13.88. Analytical HPLC:91% purity.

Example 60 Preparation ofN-(2-Dimethylamino-ethyl)3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) 3-(1H-Tetrazol-5-yl)-benzoic acid ethyl ester

A solution of 3-cyano-benzoic acid ethyl ester (2.00 g, 11.4 mmol),sodium azide (2.22 g, 34.2 mmol), and triethylamine hydrochloride (4.71g, 34.2 mmol) in 40 mL toluene was heated to 100° C. for 4.5 h. Themixture was cooled to room temperature and 150 mL of H₂O was added. Thesuspension was stirred for 10 min. and transferred to a separatoryfunnel and separated. The aqueous layer was transferred to around-bottom flask with H₂O (50 mL), cooled to 0° C. and acidified withHCl (conc). The resultant precipitate was collected by filtration,washed with H₂O, and dried in vacuo to afford 2.36 g (95%) of3-(1H-Tetrazol-5-yl)-benzoic acid ethyl ester as a white solid.

¹H NMR (DMSO-d6) δ 8.62 (s, 1H), 8.30 (d, 1H, J=8 Hz), 8.13 (d, 1H, J=8Hz), 7.76 (t, 1H, J=8 Hz), 4.36 (q. 2H, J=7 Hz) and 1.3 (t, 3H, J=7 Hz).IR (KBr, cm⁻¹) 3153, 3102, 2924, 1690, 1295, 1277, and 733. MS (ESI) m/e217. Anal. Calcd for C₁₀H₁₀N₄O₂Cl: C, 55.04; H, 4.62; N, 25.67. Found C,55.09; H, 4.64; N, 25.39.

b) 3-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid ethyl ester

To a solution of thiolacetic acid (0.65 g, 3.1 mmol) and1,3-dicyclohexylocarbodiimide (0.64 g, 3.1 mmol) in 5 mL of toluene wasadded 3-(1H-Tetrazol-5-yl)-benzoic acid ethyl ester (0.67 g, 3.1 mmol).The reaction mixture was heated to 111° C. for 20 min., concentrated invacuo and titurated with CH₂Cl₂ (5 mL). The resultant precipitate wascollected by filtration and the filtrate concentrated in vacuo. Thefiltrate was purified directly by column chromatography on silica gel(elution with 1/1 ethyl acetate and toluene) to afford 0.880 g (75%) of3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidethyl ester.

¹H NMR (CDCl₃) δ 8.7 (s, 1H), 8.2 (m, 2H), 7.6 (t, 1H, J=8 Hz), 7.3 (m,3H), 6.9 (m, 2H), 4.4 (q, 2H, J=7 Hz), 4.2 (t, 2H, 6 Hz), 4.086 (s, 2H),3.1 (t, 2H, J=6 Hz), and 1.4 (t, 3H, J=7 Hz). IR (KBr, cm⁻¹) 2935, 1719,1601, 1498, 1303, 1244. MS (ESI) m/e 385. Anal. Calcd for C₂₀H₂₀N₂O₄S:C, 62.48; H, 5.24; N, 7.29. Found C, 61.7; H, 5.34; N, 6.83.

c) 3-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

A solution of3-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidethyl ester (0.880 g, 2.29 mmol) and lithium hydroxide (0.164 g, 6.87mmol) in water (3 mL) and THF (7 mL) was stirred at room temperatureovernight. Concentrated HCl (0.59 mL) was added and the resultingprecipitate was collected by filtration and dried in vacuo to afford0.694 g (85%) of3-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidas a gold solid.

¹H NMR (DMSO-d6)

8.5 (s, 11H), 8.1 (m, 2H), 7.7 (t, 1H, J=7.7 Hz), 7.25 (m, 2H), 6.9 (m,3H), 4.2 (s, 2H), 4.2 (t, 2H, J=6.2 Hz), and 3.0 (t, 2H, J=6.3 Hz). IR(KBr, cm⁻¹) 3419, 3295, 2928, 2852, 1717, 1600, 1498, 1246, 757, 714,and 690. MS (ESI) m/e 357, 355. Anal. Calcd for Cl₈H₁₆N₂O₄S: C, 60.66;H, 4.53; N, 7.86. Found C, 58.25; H, 5.16; N, 6.99.

d)N-(2-Dimethylamino-ethyl)-3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

3-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidwas added to a nitrogen flushed vessal with CH₂Cl₂ (5 mL) followed bythe addition of oxalyl chloride (0.397 g, 3.13 mmol) and DMF (2 drops).The mixture was stirred at room temperature for 35 min., concentrated invacuo and azeotroped with CH₂Cl₂ (3×5 mL) to give3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoylchloride. N1,N1-Dimethyl-ethane-1,2-diamine was dissolved in CH₂Cl₂ (1mL) and added to a nitrogen flushed vessal.3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoylchloride was dissolved in CH₂Cl₂ (3 mL) and added dropwise. The reactionwas stirred at room temperature overnight and diluted with water,CH₂Cl₂, and NaOH (1N). The aqueous layer was extracted 2 times withCH₂Cl₂. The combined organic extracts were washed with saturated brine,dried over sodium sulfate, filtered, and concentrated. The residue waspurified by column chromatography on silica gel (elution with 95 CHCl₃/5NH₃ (2.0M in MeOH) to afford 0.167 g (63%) ofN-(2-dimethylamino-ethyl)-3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.Recrystallization from Et₂O and EtOAc gave 0.079 g (30%) of the titlecompound.

¹H NMR (DMSO-d6)

8.7 (t, 1H, J=5 Hz), 8.4 (s, 1H), 8.1 (m, 2H), 7.7 (t, 1H, J=8), 7.2 (m,2H), 6.9 (m, 3H), 4.2 (s, 2H), 4.2 (t, 2H, J=6 Hz), 3.4 (m, 2H), 3.0 (t,2H, J=6 Hz), 2.4 (t, 2H, J=7 Hz), 2.1 (s, 6H). IR (KBr, cm⁻¹) 2952,2864, 2827, 2785, 1658, 1601, 1498, 1243. MS (ESI) m/e 428, 429, 425.Anal. Calcd for C₂₂H₂₆N₄O₃S: C, 61.95; H, 6.14; N, 13.14. Found C,61.80; H, 6.23; N, 12.92. MP=64° C.

Example 61 Preparation ofN-(4-dimethylamino-butyl)-3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60, from3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.353 g, 1.0 mmol) and N1,N1-dimethyl-butane-_(1,4)-diamine (0.230 g,1.98 mmol) to give 0.346 g (77%) of the title compound.

¹H NMR (CDCl₃)

8.4 (s, 1H), 8.1, (d, 1H, J=8 Hz), 8.0 (d, 1H, J=8 Hz), 7.6, (t, 1H, J=8Hz), 7.2 (m, 3H), 6.9 (m, 2H), 4.2 (t, 2H, J=6 Hz), 4.1 (s, 2H), 3.5 (q,2H, J=5 Hz), 3.1 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), 2.2 (s, 6H), 1.8(m, 2H), 1.7 (m, 2H). IR (KBr, cm⁻¹) 2940, 2864, 2826, 2784, 1659, 1601,1549, 1498, 1243. MS (ESI) m/e 455, 453. Anal. Calcd for C₂₄H₃₀N₄O₃S: C,63.41; H, 6.65; N, 12.32. Found C, 63.52; H, 7.17; N, 12.07. MP=38–42°C.

Example 62 Preparation ofN-(3-dimethylamino-propyl)-3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60, from3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.387 g, 1.1 mmol) and N1,N1-dimethyl-propane-1,3-diamine (221 mg,2.16.mmol) to give 0.046 g (10%) ofN-(3-dimethylamino-propyl)-3-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide.

¹H NMR (CDCl₃)

9.1 (s, br, 1H), 8.4, (s, 1H), 8.14 (d, 1H, J=8 Hz), 8.1 (d, 1H, J=8Hz), 7.3 (m, 2H), 6.94 (t, 1H, J=7 Hz), 6.9 (d, 2H, J=8 Hz) 4.2 (t, 2H,J=6 Hz), 4.1 (s, 2H), 3.6 (m, 2H), 3.1), 2H, J=6 Hz), 2.6 (m, 2H), 2.4(s, 6H), 1.8 (q, 2H, J=6 Hz). IR, (KBr, cm⁻¹) 3018, 1653, 1548, 1498,1243. MS (ESI) m/e 441, 439. HPLC 100%. Anal. Calcd for C₂₃H₂₈N₄O₃S: C,62.70; H, 6.41; N, 12.72. Found C, 61.60; H, 6.19; N, 12.22. MP=88–90°C.

Example 63 Preparation ofN-(4-dimethylamino-butyl)-2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) 2-(1H-Tetrazol-5-yl)-benzoic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60a, from 2-cyano-benzoic acid methylester (2.031 g, 12.6 mmol) to give 1.87 g (73%) of2-(1H-tetrazol-5-yl)-benzoic acid methyl ester.

¹H NMR (DMSO-d6)

7.9 (m, 1H), 7.7 (m, 3H), 3.7 (s, 3H). IR (KBr, cm⁻¹) 1715, 1273. MS(ESI) m/e 203. Anal. Calcd for C₉H₈N₄O₂: C, 55.04; H, 4.62; N, 25.67.Found C, 53.68; H, 3.89; N, 28.61.

b) 2-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60b, from 2-(1H-Tetrazol-5-yl)-benzoicacid methyl ester (0.705 g, 3.45 mmol) to give 0.985 g (73%) of2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester.

¹H NMR (CDCl₃)

7.9 (m, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.2 (m, 2H), 6.95 (t, 1H, J=7Hz), 6.9 (d, 2H, J=9 Hz), 4.2 (t, 2H, J=6 Hz), 4.0 (s, 2H), 3.8 (s, 3H),3.0 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 1728, 1601, 1498, 1299, 1276, 1243.MS (ESI) m/e 371. Anal. Calcd for C₁₉H₁₈N₂O₄S: C, 61.61; H, 4.90; N,7.56. Found C, 61.41; H, 4.94; N, 7.46.

c) 2-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60c, from2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester (0.929 g, 2.51 mmol) with the exception that a gold oilformed upon treatment with conc. HCl. This material was titurated withH₂O and concentrated to dryness in vacuo to give 0.808 g (90%) of2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid.

¹H NMR(CD₃OD)

8.1 (m, 1H), 7.7 (m, 3H), 7.2 (m, 2H), 6.9 (m, 3H), 4.2 (t, 2H, J=6 Hz)4.16 (s, 2H), 3.1 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 3430, 1723, 1635,1601, 1241. MS (ESI) m/e 357, 355. Anal. Calcd for C₈H₁₆N₂O₄S: C, 60.66;H, 4.53; N, 7.86. Found C, 55.74; H, 4.48; N, 7.28.

d)N-(4-Dimethylamino-butyl)-2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60d, from2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.434 g, 1.22 mmol) and N1,N1-dimethyl-butane-1,4-diamine (0.283 g,2.44.mmol) to give 0.334 g (60%) of the title compound.

¹H NMR (CDCl₃)

8.1 (s (br), 1H), 7.9 (d, 1H, J=7 Hz), 7.5 (m, 3H), 7.3 (m, 2H), 6.95(t, 1H, J=6 Hz), 6.9 (d, 2H, J=8 Hz), 4.2 (t, 2H, J=6 Hz), 4.0 (s, 2H),3.4 (q, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.3 (t, 2H, J=6 Hz), 2.0 (s,6H), 1.66 (m, 2H), 1.6 (m, 2H). IR (KBr, cm⁻¹) 3008, 2941, 2864, 2824,2782, 1721, 1662, 1601, 1588, 1498, 1469, 1243. MS (ESI) m/e 455, 453.Anal. Calcd for C₂₄H₃₀N₄O₃S: C, 63.41; H, 6.65; N, 12.32. Found C,63.38; H, 7.01; N, 11.73. MP=62–65° C.

Example 64 Preparation ofN-(2-dimethylamino-ethyl)-2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 60d, from2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.169 g, 0.474 mmol) and N1,N1-dimethyl-ethane-1,2-diamine (0.084 g,0.948 mmol) to give 0.082 g (41%) of the title compound.

¹H NMR (CDCl₃)

7.8 (d, 1H, J=7 Hz), 7.5 (m, 3H), 7.2 (m, 2H), 6.9 (t, 1H, J=7 Hz), 6.8(d, 2H, J=8 Hz), 4.1 (t, 2H, J=6 Hz), 3.9 (s, 2H), 3.5 (m, 2H), 3.0 (t,J=6 Hz) 2.5 (s, br, 1H), 2.2 (s, 6H). IR (KBr, cm⁻¹) 3009, 1722, 1665,1601, 1498, 1470, 1402, 1242. MS (ESI) m/e 427, 425. Anal. Calcd forC₂₂H₂₆N₄O₃S: C, 61.95; H, 6.14; N, 13.13. Found C, 59.49; H, 5.91; N,12.18. MP=80–85° C.

Example 65 Preparation ofN-(3-dimethylamino-propyl)-2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

To a solution of2-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid(0.159 g, 0.45 mmol) in 3 mL THF was added 1,1′-carbonyldiimidazole(0.073 g, 0.45 mM) and 0.044 mL DMF. The mixture was heated to 60° C.for 30 min followed by stirring at room temperature for 5 min.N1,N1-Dimethyl-propane-1,3-diamine (0.091 g, 0.89 mmol) was added to themixture and stirring was continued at room temperature for 2 hours. Themixture was extracted with ethyl acetate and washed with water, brine,dried over sodium sulfate, filtered and concentrated. Purification bycolumn chromatography on silica gel (elution with chloroform and 2Mammonia in methanol gave 0.072 g (37%) of the title compound.

¹H NMR (CDCl₃) δ 7.9 (d, 1H, J=7 Hz), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (s,1H), 6.96 (t, 1H, J=7 Hz), 6.9 (d, 3H, J=39 Hz), 4.2 (7, 2H, J=6 Hz),4.0 (s, 2H), 3.5 (m, 2H), 3.0 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), 2.2(s, 6H), 1.7 (m, 2H, J=6 Hz). IR (KBr, cm⁻¹) 2928, 2864, 1722, 1684,1498, 1242. MS (ES) m/e 441. Anal. Calcd for C₂₃H₂₈N₄O₃S: C, 62.70; H,6.41; N, 12.72. Found C, 58.41; H, 6.16; N, 11.47. MP=60–65° C.

Example 66 Preparation ofdimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine

a) 4-Hydroxy-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

A solution of (2-phenoxy-ethylsulfanyl)-acetic acid (0.848 g, 4.0 mmol)and (2-ethoxy-1-ethoxycarbonyl-1,2-dihdroquinoline, ethyl1,2-dihydro-2-ethoxy-1-quinolinecarboxylate), (EEDQ), (0.989 g, 4.0mmol) in 20 mL acetonitrile and 5 mL THF were stirred together at roomtemperature for 1 hr. 4-Hydroxy-benzoic acid hydrazide (0.608 g, 4.0mmol) was added and the mixture was sonicated for 2 hrs and stirred atroom temperature for 16 hrs. The mixture was concentrated to low volumeand extracted with ethyl acetate. The organic extract was washed with 1NHCl, H₂O, NaHCO₃, brine, dried over magnesium sulfate, filtered, andconcentrated to dryness to give 1.28 g (92%) of 4-hydroxy-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide.

¹H NMR (DMSO-d6) δ 10.2 (s, 1H), 10.1 (s, 1H), 10.0 (s, 1H), 7.7 (d, 2H,J=9 Hz), 7.3 (m, 2H), 6.9 (m, 3H), 6.8 (d, 2H, J=9 Hz), 4.2 (t, 2H, J=6Hz), 3.3 (m, 2H), 3.0 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 3305, 3201, 3003,2918, 2867, 1696, 1623, 1609, 1584, 1517, 1287, 1242, 1229. MS (ESI) m/e347, 345. Anal. Calcd for C₁₇H₁₈N₂O₄S: C, 58.95; H, 5.24; N, 8.09. FoundC, 58.37; H, 5.51; N, 7.19.

b) 4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol

A solution of 4-hydroxy-benzoic acidN-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (4.87 g, 14.1 mmol),triphenylphosphine (7.38 g, 28.1 mmol), and triethylamine (5.14 g, 50.7mmol) were stirred together in acetonitrile (15 mL). Carbontetrachloride (9.17 g, 57.9 mmol) was added and the mixture was stirredat room temperature for 3 hrs. The material was concentrated to lowvolume and diluted with hexane (100 mL), ethyl acetate (6 mL), andethanol (25 mL). The mixture was sonnicated for 5 minutes and aprecipitate formed. The solid was collected and dried in vaccuo (30°C.). The solid was slurried with 1N HCl, collected and dried to give3.149 g (68%) of the title compound.

¹H NMR (DMSO-d6) δ 7.8 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 6.9 (m,5H), 4.2 (m, 4H), 3.0 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 3410, 1762, 1611,1601, 1498, 1242, 1226, 1174, 752. MS (ESI) m/e 329, 327. Anal. Calcdfor C₁₇H₁₆N₂O₃S: C, 62.18; H, 4.91; N, 8.53. Found C, 61.99; H, 5.00; N,7.92. M.P.=172–175° C.

c) Preparation ofdimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine

A solution of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.214 g, 0.652 mmol) and 60% NaH (0.075 g, 1.95 mmol) was stirred at 5°C. in 10 mL DMF for 2 min. at which time(2-chloro-ethyl)-dimethyl-amine, hydrochloride (0.140 g, 0.978 mmol) wasadded and the mixture was stirred at 100° C. for 2.5 hours. Theresultant mixture was extracted 2 times with ethyl acetate and washedwith water, brine, dried over sodium sulfate and concentrated to give0.243 g of crude product. This was purified directly by columnchromatography on silica gel (elution with 1/1 ethyl acetate, toluenefollowed by chloroform/2M ammonia in methanol) to give a yellow oilwhich was recrystallized from ethyl ether and ethyl acetate to give0.098 g (38%) of the title compound.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9Hz), 6.9 (m, 3H), 4.1 (m, 6H), 3.0 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=5 Hz),2.2 (s, 6H). IR (KBr, cm⁻¹) 1616, 1499, 1466, 1253, 1242, 1177, 756. MSESI) m/e 400.9. Anal. Calcd for C₂₁H₂₅N₃O₃S: C, 63.14; H, 6.31; N,10.52. Found C, 62.92; H, 6.09; N, 10.38. MP=62–64° C.

Example 67 Preparation ofdimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.548 g, 1.67 mmol) and (3-chloro-propyl)-dimethyl-amine, hydrochloride(396 mg, 2.5 mmol) to give 0.288 g (42%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.3 (t, 2H, J=7 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.4 (t, 2H,J=7 Hz), 2.1 (s, 6H), 1.9 (m, 2H). IR (KBr, cm⁻¹) 2934, 1612, 1601,1503, 1491, 1466, 1253, 1243, 1178, 762. MS (ESI) m/e 414. Anal. Calcdfor C₂₂H₂₇N₃O₃S: C, 63.90; H, 6.58; N, 10.16. Found C, 63.55; H, 6.50;N, 10.04. MP=70° C.

Example 68 Preparation ofdimethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine

a)2-[4-(4-Chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

A solution of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.202 g, 0.615 mmol), 1-bromo-4-chloro-butane (0.158 g, 0.922 mmol),and potassium carbonate (0.195 g, 1.41 mM) was refluxed in 5 mL acetoneovernight. The solid was removed by filtration and the filtrateconcentrated to dryness. Recrystallization of the filtrate from etherand ethyl acetate gave 0.127 g (49%) of2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole.

¹H NMR (DMSO-d6)

7.8 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.1 (t, 2H, J=6 Hz), 3.7 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz),1.9 (m, 4H). IR (KBr, cm⁻¹) 1614, 1604, 1586, 1499, 1253, 1242, 1176. MS(ESI) m/e 419, 417. Anal. Calcd for C₂₁H₂₃ClN₂O₃S: C, 61.80; H, 6.09; N,6.26. Found C, 59.82; H, 5.67; N, 6.41.

b)Dimethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine

A solution of2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.127 g, 0.303 mmol), dimethyl amine (2M THF, 3.8 mL, 7.58 mmol), NaI(0.004 g, 0.0236 mmol), and NaHCO₃ (0.071 g, 0.84 mmol) in 4 mL DMF washeated to 80° C. overnight in a sealed tube. The mixture was extractedwith ethyl acetate followed by washing with water, brine, dried oversodium sulfate and concentrated to dryness. The residue was purifieddirectly by column chromatography on silica gel (elution with ethylacetate/toluene followed by 90% chloroform/10% 2M ammonia in methanol)to give 0.090 g (70%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2h, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.0 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.2 (t, 2H, J=7 Hz),2.1 (s, 6H), 1.7 (m, 2H), 1.5 (m, 2H). IR (KBr, cm⁻¹) 2763, 1612, 1501,1259, 1246, 1177, 999, 841. MS (ESI) m/e 428. Anal. Calcd forC₂₃H₂₉N₃O₃S: C, 64.61; H, 6.84; N, 9.83. Found C, 64.60; H, 6.85; N,9.69. MP=62–63° C.

Example 69 Preparation ofdimethyl-(5-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-pentyl)-amine

a)2-[4-(5-Chloro-pentyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.304 g, 0.926 mmol), and 1-bromo-5-chloro-pentane (0.250 g, 1.38 mmol)to give 0.260 g (65%) of2-[4-(5-chloro-pentyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz) 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m 4H), 4.0 (t, 2H, J=6 Hz), 3.6 (t, 2H, J=7 Hz), 3.0 (t, 2H, J=6 Hz),1.8 (m, 4H), 1.5 (m, 2H). IR (KBr, cm⁻¹) 1611, 1503, 1490, 1258, 1244,1178, 1005, 844, 765. MS (ESI) m/e 433. Anal. Calcd for C₂₂H₂₅N₂ClO₃S:C, 61.03; H, 5.82; N, 6.47. Found C, 59.71; H, 5.75; N, 6.34.

b)Dimethyl-(5-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-pentyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(5-chloro-pentyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.210 g, 0.487 mmol) to give 0.111 g (52%) of the title compound.

¹H NMR (DMSO-d6)

7.8 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.1(m, 4H), 4.0 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz) 2.2 (t, 2H, J=7 Hz),2.1 (s, 6H), 1.7 (m, 2H), 1.4 (m, 4H). IR (KBr, cm⁻¹) 2941, 1602, 1610,1500, 1466, 1253, 1175, 1032, 835, 751. MS (ESI) m/e 442. Anal. Calcdfor C₂₄H₃₁N₃O₃S: C, 65.28; H, 7.08; N, 9.51. Found C, 65.47; H, 7.03; N,9.35. MP 51–54° C.

Example 70 Preparation ofdimethyl-(6-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-hexyl)-amine

a)2-[4-(6-Chloro-hexyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.243 g, 0.739 mmol) and 1-bromo-6-chloro-hexane (0.221 g, 1.11 mmol)to give 0.266 g (81%) of2-[4-(6-chloro-hexyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.0 (t, 2H, J=6 Hz), 3.6 (t, 2H, J=7 Hz), 3.0 (t, 2H, J=6 Hz),1.7 (m, 4H), 1.4 (m, 4H). IR (KBr, cm⁻¹) 3456, 2936, 2866, 1615, 1586,1503, 1466, 1258, 1239, 1176, 1007, 843, 764. MS (ES) m/e 447. Anal.Calcd for C₂₃H₂₇N₂ClO₃S: C, 61.80; H, 6.09; N, 6.27. Found C, 61.62; H,5.55; N, 6.21.

b)Dimethyl-(6-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-hexyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(6-chloro-hexyloxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.266 g, 0.595 mmol) to give 0.116 g (43%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.0 (t, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.2 (t, 2H, J=7 Hz), 2.1(s, 6H), 1.7 (m, 2H), 1.4 (m, 4H), 1.3 (m, 2H). IR (KBr, cm⁻¹) 1611,1602, 1587, 1500, 1466, 1249, 1175, 1024, 756. MS (ESI) m/e 456. Anal.Calcd for C₂₅H₃₃N₃O₃S: C, 65.90; H, 7.30; N, 9.22. Found C, 65.37; H,7.16; N, 9.08.

Example 71 Preparation ofdimethyl-(7-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-heptyl)-amine

a)7-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-heptan-1-ol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.260 g, 0.792 mmol) and 7-bromo-heptan-1-ol (0.232 g, 1.19 mmol) togive 0.164 g (47%) of7-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-heptan-1-ol.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, 9 Hz), 6.9 (m, 3H), 4.3(s, 1H) 4.2 (m, 4H), 4.0 t, 2H, J=6 Hz), 3.3 (m, 2H), 3.0 (t, 2H, J=6Hz), 1.7 (m, 2H), 1.2–1.4 (m, 8H). IR (KBr, cm⁻¹) 3622, 3011, 2936,2861, 1613, 1602, 1499, 1469, 1256, 1224, 1174, 1034. MS (ES) m/e 443.Anal. Calcd for C₂₄H₃₀N₂O₄S: C, 65.13; H, 6.83; N, 6.33. Found C, 63.3;H, 6.72; N, 5.91.

b)Dimethyl-(7-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-heptyl)-amine

Methanesulfonyl chloride (0.046 g, 0.407 mmol) was added dropwise to asolution of7-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-heptan-1-ol(0.164 g, 0.374 mmol) and triethylamine (0.045 g, 0.444 mmol) indichloromethane (20 mL). The mixture was stirred at room temperature for5 min and concentrated to dryness to give the crude mesylate. The crudesolid was dissolved in methanol (10 mL) in a sealed tube anddimethylamine was added (5 mL). The mixture was heated to 80° overnightand concentrated to dryness. The crude solid was dissolved in ethylacetate and washed with water, brine, dried over sodium sulfate,filtered and concentrated to dryness. The solid was purified directly bycolumn chromatography on silica gel (elution with 1/1 ethyl acetatefollowed by 90% CHCl₃ and 10% 2M NH₃ in methanol to give 0.063 g (36%)of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.0 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.2 (t, 2H, J=7 Hz),2.1 (s, 6H), 1.7 (m, 2H), 1.2–1.4 (m, 8H). IR (KBr, cm⁻¹) 2925, 2854,2762, 1611, 1500, 1254, 1175, 750. MS (ES) m/e 470. Anal. Calcd forC₂₆H₃₅N₃O₃S: C, 66.49; H, 7.51; N, 8.95. Found C, 64.78; H, 7.57; N,8.44. HPLC 90%. MP=39–40° C.

Example 72 Preparation of1-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.202 g, 0.615 mmol) and 1-(2-chloroethyl)piperidine monohydrochloride(0.17 g, 0.922 mmol) to give 0.059 g (22%) of the title compound.

¹H NMR (DMSO-d6) δ 7.8 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H) 4.2 (m, 6H), 3.0 (t, 2H, J=6 Hz), 2.6 (m, 2H), 2.4(m, 4H), 1.5 (m, 4H), 1.4 (m, 2H). IR (KBr, cm⁻¹) 2940, 1613, 1499,1255, 1245, 1175. MS (ESI) m/e 440. Anal. Calcd for C₂₄H₂₉N₃O₃S: C,65.58; H, 6.65; N, 9.56. Found C, 64.56; H, 6.61; N, 9.42. HPLC 100%.MP=70° C.

Example 73 Preparation ofdiisopropyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[[1,3,4]oxadiazol-2-yl]-phenol(0.223 g, 0.679 mmol) and (2-chloro-ethyl)-diisopropyl-amine,monohydrochloride (0.204 g, 1.02 mmol) to give 0.178 g (58%) of thetitle compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.0 (t, 2H J=7 Hz), 3.0 (m, 4H), 2.8 (t, 2H, J=7 Hz),1.0 (d, 12H, J=6 Hz). IR (KBr, cm⁻¹) 3632, 3432, 3013, 2945, 2838, 1602,1464, 13333, 1242. MS (ESI) m/e 456. Anal. Calcd for C₂₅H₃₃N₃O₃S: C,65.90; H, 7.30; N, 9.22. Found C, 65.68; H, 7.16; N, 9.17. MP=42–45° C.

Example 74 Preparation of4-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-morpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.266 g, 0.81 mM) and 4-(2-chloro-ethyl)-morpholine monohydrochloride(0.226.g, 1.22 mmol) to give 0.225 g (63%) of the title compound.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=8 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H), 4.2 (m, 6H), 3.6 (t, 4H, J=4 Hz), 3.0 (t, 2H, J=6Hz), 2.7 (t, 2H, J=6 Hz), 2.5 (m, 4H). IR (KBr, cm⁻¹) 1613, 1601, 1588,1499, 1302, 1253, 1175, 1117. MS (ESI) m/e 442, 440.5. Anal. Calcd forC₂₃H₂₇N₃O₄S: C, 62.56; H, 6.16; N, 9.51. Found C, 62.20; H, 6.02; N,9.39. MP=70–72° C.

Example 75 Preparation of1-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[S-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.218 g, 0.664 mmol) and 1-(3-chloro-propyl)-piperidine,monohydrochloride (0.197 g, 0.996 mmol) to give 0.055 g (18%) of thetitle compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=8 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.1 (t, 2H, J=7 Hz), 3.0 (t, 2H, J=6 Hz), 2.4–2.3 (m, 6H), 1.9(t, 2H, J=7 Hz), 1.5 (m, 4H), 1.4 (m, 2H). IR (KBr, cm⁻¹) 3008, 2939,1614, 1601, 1499, 1303, 1256, 1245, 1175, 839. MS (ESI) m/e 454. Anal.Calcd for C₂₅H₃₁N₃O₄S: C, 65.58; H, 6.65; N, 9.55. Found C, 65.34; H,6.65; N, 8.95. MP=65° C.

Example 76 Preparation of2-(2-phenoxy-ethylsulfanylmethyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 66c, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.216 g, 0.658 mmol) and 1-(2-chloro-ethyl)-pyrrolidine,monohydrochloride (0.168 g, 0.987 mmol) to give 0.052 g (18%) of thetitle compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=8 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=8 Hz), 6.9 (m,3H), 4.2 (m, 6H), 3.0 (t, 2H, J=6 Hz), 2.8 (m, 2H), 2.5 (m, 4H), 1.6(m,4H). IR (KBr, cm⁻¹) 1614, 1500, 1246, 1175. MS (ESI) m/e 426. Anal.Calcd for C₂₃H₂₇N₃O₃S: C, 64.92; H, 6.40; N, 9.87. Found C, 64.92; H,6.44; N, 9.76. MP=65° C.

Example 77 Preparation ofmethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

a)2-[4-(3-Chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(2.396 g, 7.30 mmol) and 1-bromo-3-chloro-propane (1.72 g, 10.9 mmol) togive 1.60 g (54%) of2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 6H), 3.8 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.2 (m, 2H).MS (ESI) m/e 405.

b)Methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.247 g, 0.61 mmol) and methylamine (40% weight in water, 2 mL, 26mmol). HPLC chromatography on the material previously purified by silicachromatography and combination of various lots gave 190 mg of materialas the TFA salt which was desalted to the free amine by washing with 1NNaOH, dried over sodium sulfate, filtered and concentrated to dryness togive 0.088 g (14%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.6 (t, 2H,J=7 Hz), 2.3 (s, 3H), 1.8 (m, 2H). IR (KBr, cm⁻¹) 1677, 1611, 1500,1254, 1205, 1176, 1131, 835, 754, 722. MS (ESI) m/e 400, 398. Anal.Calcd for C₂₁H₂₅N₃O₃S: C, 63.14; H, 6.31; N, 10.52. Found C, 61.78; H,5.92; N, 9.91. MP=40–44° C. HPLC 100%.

Example 78 Preparation ofdiethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.230 g, 0.568 mmol) and diethylamine (1.04 g, 14.2 mmol) to give 0.127g (50%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.5 (m, 4H),1.8 (t, 2H, J=6 Hz), 0.9 (t, 6H, J=7 Hz). IR (KBr, cm⁻¹) 2973, 1613,1602, 1499, 1256, 1245, 1174. MS (ESI) m/e 442. Anal. Calcd forC₂₄H₃₁N₃O₃S: C, 65.28; H, 7.08; N, 9.52. Found C, 65.19; H, 7.17; N,9.41. MP=27–31° C.

Example 79 Preparation of1-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperazine

a)4-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperazine-1-carboxylicacid tert-butyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.241 g, 0.595.mmol) and piperazine-1-carboxylic acid tert-butyl ester(0.111 g, 0.595 mmol) to give 0.096 g (29%) of4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperazine-1-carboxylicacid tert-butyl ester.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.1 (d, 2H, J=9 Hz), 6.9 (m, 3H), 4.2(m, 4H), 4.1 (t, 2H, J=5 Hz), 3.3 (m, 4H), 3.0 (t, 2H, J=6 Hz), 2.4 (m,2H), 2.3 (m, 4H), 1.9 (m, 2H), 1.4 (s, 91). MS (ESI) m/e 555. Anal.Calcd for C₂₉H₃₈N₄O₅S: C, 62.79; H, 6.90; N, 10.10. Found C, 61.53; H,6.70; N, 9.73. HPLC 100%.

b)1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperazine

A solution of4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperazine-1-carboxylicacid tert-butyl ester (20a) (0.115 g, 0.20 mmol) and trifluoroaceticacid (5 mL) in 5 mL CH₂Cl₂ was stirred at 5° C. for 1 hr. The reactionmixture was concentrated to dryness and extracted into ethyl acetate.The organic extract was washed with NaHCO₃, brine, dried over sodiumsulfate, filtered and concentrated to give 0.065 g which was purifieddirectly by column chromatography on silica gel (elution with ethylacetate and toluene followed by 90 chloroform/10 ammonia (2M methanol)to give 0.044 g (47%) of the title product.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz)), 7.1 (d,2H, J=9 Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H,J=6 Hz), 2.6 (m, 4H), 2.4 (t, 2H, J=7 Hz), 2.3 (m, 4H), 1.8 (m, 2H). MS(ESI) m/e 455. HPLC 100%.

Example 80 Preparation of2-(2-phenoxy-ethylsulfanylmethyl)-5-[4-(4-pyrrolidin-1-yl-butoxy)-phenyl]-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.235 g, 0.561 mmol) and pyrrolidine (0.099 g, 1.4 mmol) to give 0.145g (57%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz)), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.4 (m, 6H),1.8 (m, 2H), 1.7 (m, 4H), 1.6 (m, 2H). IR (KBr, cm⁻¹) 2932, 2563, 2467,1617, 1500, 1257, 1248. MS (ESI) m/e 454. Anal. Calcd for C₂₅H₃₁N₃O₃S:C, 66.20; H, 6.89; N, 9.26. Found C, 65.98; H, 6.90; N, 9.13. M.P.=45°.

Example 81 Preparation of1-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.232 g, 0.554 mmol) and piperidine (0.118 g, 1.38 mmol) to give 0.041g (16%) of the title compound.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz)), 7.1 (d,2H, J=9 Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H,J=6 Hz), 2.3 (m, 6H), 1.7 (m, 2H), 1.6 (m, 2H), 1.5 (m, 4H), 1.4 (m,2H). IR (KBr, cm⁻¹) 2923, 1610, 1601, 1586, 1500, 1467, 1304, 1256,1248, 1174, 1031. MS (ESI) m/e 470. Anal. Calcd for C₂₆H₃₃N₃O₃S: C,66.78; H, 7.11; N, 8.99. Found C, 66.16; H, 6.91; N, 8.80. M.P.=57–62°C.

Example 82 Preparation of4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-thiomorpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.248 g, 0.612 mmol) and thiomorpholine (0.157 g, 1.53 mM) to give0.136 g (47%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz)), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.6 (m, 8H),2.4 (t, 2H, J=7 Hz), 1.9 (m, 2H). IR (KBr, cm⁻¹) 2922, 2810, 2775, 1611,1601, 1590, 1502, 1491, 1468, 1256, 1244, 1176, 837, 766. MS (ESI) m/e472, 470. Anal. Calcd for C₂₄H₂₉N₃O₃S₂: C, 61.12; H, 6.20; N, 8.91.Found C, 60.85; H, 6.26; N, 8.75. M.P.=85° C.

Example 83 Preparation of1-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-azepane

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.213 g, 0.526 mmol) and azepane (1.30 g, 13.1 mmol) to give 0.103 g(42%) of the title compound.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6Hz), 2.6 (m, 6H), 1.8 (m, 2H), 1.5 (m, 8H). IR (KBr, cm⁻¹) 2927, 2905,1614, 1497, 1468, 1251, 1181, 1171, 1036, 1029, 747, 689. MS (ESI) m/e468. Anal. Calcd for C₂₆H₃₃N₃O₃S: C, 66.78; H, 7.11; N, 8.98. Found C,66.48; H, 6.94; N, 8.91. M.P.=50° C.

Example 84 Preparation of3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propylamine

a)(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-carbamicacid tert-butyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.501 g, 1.52 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester(0.545 g, 2.28 mmol) to give the BOC protected product which waspurified by column chromatography on silica gel (elution with ethylacetate/toluene) to give 0.617 g (84%) of the(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-carbamicacid tert-butyl ester.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.0 (t, 2H, J=6 Hz), 3.1 (q, 2H, J=6 Hz), 3.0 (t, 2H,J=6 Hz), 1.8 (m, 2H), 1.4 (s, 9H). IR (KBr, cm⁻¹) 3400, 1692, 1609,1524, 1501, 1248, 1242, 1176, 844, 764. MS (ESI) m/e 486. Anal. Calcdfor C₂₅H₃₁N₃O₅S: C, 70.12; H, 5.23; N, 9.08. Found C, 69.86; H, 5.19; N,8.92.

b)3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propylamine

A solution of(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-carbamicacid tert-butyl ester (0.600 mg, 1.23 mmol) in TFA (7 mL) and CH₂Cl₂, (5mL) was stirred at 5° C. for 1 hr. The reaction mixture was concentratedto dryness and extracted into ethyl acetate. The organic extract waswashed with NaHCO₃, brine, dried over Na₂SO₄, filtered and concentratedto give 0.300 g. Elemental analysis indicated the presence of fluorine.The material was dissolved in water, ethyl acetate and a minimum amountof methanol to solubilize the material. The mixture was washed with 1NNaOH, dried over sodium sulfate, and concentrated to give 0.183 g, (38%)of the3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propylamine.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,31), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.7 (t, 2H,J=7 Hz), 1.8 (m, 2H). IR (KBr, cm⁻¹) 3004, 2972, 2928, 2902, 1616, 1504,1474, 1252, 1175, 833. MS (ESI) m/e 386. Anal. Calcd for C₂₀H₂₃N₃O₃S: C,62.31; H, 6.01; N, 10.90. Found C, 61.08; H, 5.99; N, 10.49. HPLC 100%.M.P.=30–35°.

Example 85 Preparation ofdiethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.206 g, 0.627 mmol) and (2-bromo-ethyl)-diethyl-amine hydrobromide togive 0.041 g (15%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.8 (m, 2H),2.6 (m, 4H), 1.0 (t, 6H, J=7 Hz). IR (KBr, cm⁻¹) 1614, 1498, 1258, 1176,1172, 752. MS (ESI) m/e 429. Anal. Calcd for C₂₃H₂₉N₃O₃S: C, 64.61; H,6.84; N, 9.83. Found C, 64.37; H, 6.85; N, 9.77. M.P.=32–35° C.

Example 86 Preparation of1-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-azepane

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.197 g, 0.599 mmol) and 1-(2-chloro-ethyl)-azepane hydrochloride(0.178 g, 0.899 mmol) to give crude material that was purified directlyby column chromatography on silica gel (elution with ethylacetate/toluene followed by 90% chloroform/10% 2M NH₃ in methanol togive 0.216 g (79%) of the title compound.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6Hz), 2.9 (m, 2H), 2.7 (m, 4H), 1.5 (m, 8H). IR (KBr, cm⁻¹) 2917, 1613,1604, 1500, 1261, 1247, 1176, 749. MS (ESI) m/e 454. Anal. Calcd forC₂₅H₃₁N₃O₃S: C, 66.20; H, 6.89; N, 9.26. Found C, 66.17; H, 6.96; N,9.16. M.P.=40° C.

Example 87 Preparation of4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-morpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.222 g, 0.548 mmol) and morpholine (0.119 g, 1.37 mmol) to give 0.078g (31%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.6 (t, 4H, J=4 Hz) 3.0 (t, 2H,J=6 Hz), 2.4 (t, 2H, J=7 Hz), 2.3 (m, 4H), 1.9 (m, 2H). IR (KBr, cm⁻¹)3436, 2965, 2943, 2926, 2863, 2810, 1609, 1500, 1468, 1297, 1256, 1242,1174, 1115, 838, 764. MS (ESI) m/e 456, 454. Anal. Calcd forC₂₄H₂₉N₃O₄S: C, 63.27; H, 6.41; N, 9.22. Found C, 63.06; H, 6.60; N,9.04. M.P.=65° C.

Example 88 Preparation of2-(2-phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.222 g, 0.548 mmol) and pyrrolidine (0.097 g, 1.37 mmol) to give 0.131g (54%) of the title compound.

¹H NMR DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.6 (t, 2H,J=7 Hz), 2.5 (m, 4H), 1.9 (m, 2H), 1.7 (m, 4H). IR (KBr, cm⁻¹) 2972,2944, 2928, 2865, 2792, 1613, 1584, 1500, 1478, 1466, 1402, 1253, 1183,1152, 1006, 849, 757. MS (ESI) m/e 440, 439. Anal. Calcd forC₂₄H₂₉N₃O₃S: C, 65.58; H, 6.65; N, 9.56. Found C, 65.28; H, 6.70; N,9.45. M.P.=70° C.

Example 89 Preparation of1-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-azepane

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.227 g, 0.542 mmol) and azepane (0.56 g, 5.64 mmol) to give 0.091 g(35%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.5 (m, 6H),1.7 (m, 2H), 1.5 (m, 10H). IR (KBr, cm⁻¹) 2930, 1610, 1493, 1248, 1175,837. MS (ESI) m/e 482, 480. Anal. Calcd for C₂₇H₃₅N₃O₃S: C, 67.33; H,7.32; N, 8.72. Found C, 67.35; H, 7.25; N, 8.91. M.P.=35–38° C.

Example 90 Preparation of4-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-thiomorpholine

a)2-[4-(2-Chloro-ethoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(1.491 g, (4.54.mmol) and 1-bromo-2-chloro-ethane (0.98 g, 6.81 mmol) togive 1.216 g (68%) of2-[4-(2-chloro-ethoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.3 (t, 2H, J=5 Hz), 4.2 (m, 4H), 4.0 (t, 2H, J=5 Hz), 3.0 (t, 2H,J=6 Hz). IR (KBr, cm⁻¹) 3439, 2965, 2929, 2916, 1619, 1603, 1586, 1499,1465, 1249, 1177, 1088, 1023, 1008, 756. MS (ESI) m/e 391. Anal. Calcdfor C₁₉H₁₉ClN₂O₃S: C, 58.38; H, 4.90; N, 7.17. Found C, 58.27; H, 5.01;N, 7.07.

b)4-(2-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-ethyl)-thiomorpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(2-chloro-ethoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.215 g, 0.55 mmol) and thiomorpholine (0.141 g, 1.37 mmol) to give0.066 g (26%) of the title product.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 6H), 3.0 (t, 2H, J=6 Hz) 2.8 (m, 6H), 2.6 (m, 4H). IR (KBr,cm⁻¹) 2926, 2807, 1614, 1503, 1459, 1297, 1253, 1173, 834, 754. MS (ES)m/e 458, 456. Anal. Calcd for C₂₃H₂₇N₃O₃S₂: C, 60.37; H, 5.95; N, 9.18.Found C, 59.64; H, 5.61; N, 8.94. M.P.=60° C. HPLC 100%.

Example 91 Preparation of1-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-[1,4]diazepane

a)4-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68a, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.223 g, 0.679 mmol) and4-(3-chloro-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(0.376 g, 1.36 mmol) to give crude material that was purified directlyby column chromatography on silica gel (elution with ethylacetate/toluene followed by 90% chloroform/10% 2M NH₃ in methanol) togive 0.49 g (100%) of4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=7 Hz), 3.6 (t, 2H, J=6 Hz), 3.0 (t, 2H,J=6 Hz) 2.6 (m, 4H), 1.8 (m, 4H), 1.6 (m, 4H), 1.4 (s, 9H). MS (ESI) m/e569.

b)1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-[1,4]diazepane

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 79b, from4-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.49 g, 0.862 mmol) and trifluoroacetic acid (5mL) to give 0.136 g (34%) of the title product.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.3 (m, 2H), 3.0 (t, 2H, J=6 Hz)2.8 (m, 3H), 2.6 (m, 6H), 1.8 (m, 2H), 1.6 (m, 2H). IR (KBr, cm⁻¹) 2337,1671, 1613, 1499, 1256, 1245, 1175. MS (ESI) m/e 469. Anal. Calcd forC₂₅H₃₂N₄O₃S: C, 64.08; H, 6.88; N, 11.95. Found C, 58.41; H, 6.35; N,10.64. HPLC 100%.

Example 92 Preparation of4-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-morpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.225 g, 0.537 mmol) and morpholine (0.117 g, 1.34 mmol) to give 0.144g (57%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.5 (m, 4H), 3.0 (t, 2H, J=6 Hz)2.3 (m, 6H), 1.8 (m, 2H), 1.6 (m, 2H). IR (KBr, cm⁻¹) 2935, 2852, 2811,1611, 1499, 1303, 1249, 1174, 1118, 836. MS (ESI) m/e 470, 468. Anal.Calcd for C₂₅H₃₁N₃O₄S: C, 63.94; H, 6.65; N, 8.95. Found C, 63.83; H,6.72; N, 8.93. M.P.=64–67° C.

Example 93 Preparation ofdiethyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.225 g, 0.537 mmol) and diethyl amine (0.989 g, 13.4 mmol) to give0.090 g (37%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz) 2.4 (m, 6H),1.7 (m, 2H), 1.6 (m, 2H), 1.0 (t, 6H, J=7 Hz). IR (KBr, cm⁻¹) 2929,2799, 1610, 1500, 1248, 1174, 1005, 837. MS (ESI) m/e 456. Anal. Calcdfor C₂₅H₃₃N₃O₃S: C, 65.90; H, 7.30; N, 9.22. Found C, 63.98; H, 7.08; N,9.72. M.P.=35–38° C. HPLC 99%.

Example 94 Preparation of4-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-thiomorpholine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 68b, from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.313 g, 0.747 mmol) and thiomorpholine (0.154 g, 1.49 mmol) to give0.219 g (60%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 41), 4.1 (t, 2H, J=6 Hz), 3.0 (t, 2H, J=6 Hz), 2.6 (m, 8H),2.3 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H). IR (KBr, cm⁻¹) 3000, 2873, 2816,1613, 1588, 1499, 1256, 1245, 1174, 1006, 839. MS (ES) m/e 486, 484.Anal. Calcd for C₂₅H₃₁N₃O₃S₂: C, 61.83; H, 6.43; N, 8.65. Found C,61.66; H, 6.44; N, 8.59. M.P.=58° C.

Example 95 Preparation ofN-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-methanetriamine,trifluoroacetic acid salt

a)N-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-methanetriamine,di-carboxylic acid tert-butyl ester

A solution of3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propylamine(Example 85b) (0.142 g, 0.368 mmol) and1,3-bis(t-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.112 g, 0.387mmol) in acetonitrile (7 mL) was stirred at room temperature overnight.The mixture was diluted with ethyl acetate and washed with saturatedNaHCO₃. The aqueous layer was extracted once with ethyl acetate. Thecombined organics were washed with water, brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by columnchromatography on silica gel (elution with ethyl acetate/toluene) togive 0.119 g (52%) ofN-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-methanetriamine,di-carboxylic acid tert-butyl ester (40a).

¹H NMR (DMSO-d6)

8.5 (m, 1H), 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.5 (m, 2H), 3.0 (t,2H, J=6 Hz) 2.0 (m, 2H), 1.5 (s, 9H), 1.4 (s, 9H). MS (ESI) m/e 628.

b)N-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-methanetriamine,trifluoroacetic acid salt

N-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-methanetriamine,di-carboxylic acid tert-butyl ester (0.253 g, 0.403 mmol) was dissolvedin CH₂Cl₂ (5 mL) and cooled to 5° C. Trifluoroacetic acid (5 mL) wasadded and the mixture was stirred at 5° C. for 1 hr and at roomtemperature for 1 hr. The mixture was concentrated to dryness, dilutedwith ethyl acetate and washed with 1N NaOH. The aqueous layer wasextracted twice with ethyl acetate. The combined organic extracts werewashed with water, brine, dried over sodium sulfate, filtered, andconcentrated to 0.073 g. Due to low recovery, the aqueous layer wasextracted 4 times with CH₂Cl₂ and the combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentratedto 0.186 g. The combined residues were purified by column chromatographyon silica gel (elution with ethyl acetate/toluene followed by 90%chloroform/10% 2M NH₃ in methanol) to give 0.106 g that wasrecrystallized from 1 mL ethyl acetate and 5 mL ethyl ether to give0.075 g (34%) of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.6 (m, 1H), 7.2 (m, 3H), 7.1 (m, 3H), 7.0 (s, 1H),6.9 (m, 3H), 4.2 (m, 4H), 4.1 (t, 2H, J=6 Hz), 3.3 (m, 2H), 3.0 (t, 2H,J=6 Hz), 2.0 (m, 2H). IR (KBr, cm⁻¹) 3400, 3110, 1674, 1636, 1612, 1500,1252, 1205, 1176, 1136. MS (ESI) m/e 428. Anal. Calcd for C₂₃H₂₆N₅F₃O₅S:C, 51.01; H, 4.84; N, 12.93; F, 10.52. Found C, 45.58; H, 4.91; N,13.21; F, 11.96. M.P.=100° C. HPLC 100%.

Example 96 Preparation of2-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

A mixture of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.346 g, 1.05 mmol) and 60% NaH (0.121 g, 3.15 mmol) was stirred at 5°C. for 2 minutes in DMF (5 mL). Added2-(2-chloro-ethyl)-1-methyl-pyrrolidine (0.291 g, 1.58 mmol) and heatedthe mixture to 100° C. for 10 hrs. Diluted with ethyl acetate and water.The aqueous layer was extracted twice with ethyl acetate. The combinedorganic extracts were washed 3× water, brine, dried over sodium sulfate,filtered and concentrated. The residue was purified by columnchromatography on silica gel (elution with ethyl acetate/toluenefollowed by 90% chloroform/10% 2M NH₃ in methanol) to give 0.054 g,(12%) of the title compound and material that was a mixture of 2products, one being the title compound and a second product of thereaction Example 97), see procedure for Example 97.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H), 4.2 (m, 4H), 4.1 (m, 2H), 3.0 (m, 3H), 2.3 (s,3H), 2.2 (m, 1H), 2.1 (m, 2H), 2.0 (m, 1H), 1.7 (m, 3H), 1.5 (m, 1H). IR(KBr, cm⁻¹) 3410, 3000, 2910, 2800, 1610, 1500, 1468, 1257, 1241, 1173,764. MS (ESI) m/e 440. Anal. Calcd for C₂₄H₂₉N₃O₃S: C, 65.58; H, 6.65;N, 9.56. Found C, 63.09; H, 6.22; N, 8.96. M.P.=46–50° C. HPLC 94%.

Example 97 Preparation of1-methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-azepane

Prepared in the same manner as exemplified in Example 96 and isolated asa by-product of the reaction mixture. The mixture isolated viachromatography from procedure 96 was purified a second time using aWaters Preparatory 2000 with a Kromasil silica column (5×25 cm) (elutionwith 50/50 ethyl acetate/dichloromethane/1% dimethylethylamine to give0.209 g (12%) of the title compound and 0.200 g (12%) of the compound ofExample 96.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.7 (m, 1H), 4.2 (m, 4H), 3.0 (m, 2H), 2.65 (m, 1H), 2.6 (m, 2H),2.5 (m, 1H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 1H), 1.8 (2H), 1.6 (m,1H). IR (KBr, cm⁻¹) 2923, 1612, 1602, 1587, 1499, 1465, 1295, 1237,1174, 1002. MS (ESI) m/e 440. Anal. Calcd for C₂₄H₂₉N₃O₃S: C, 65.58; H,6.65; N, 9.56. Found C, 66.35; H, 6.83; N, 9.05. M.P.=60–61° C. HPLC100%.

Example 98 Preparation of4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-pyridine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 96, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.303 g, 0.923 mmol) and 4-bromomethyl-pyridine hydrobromide salt(0.350 g, 1.38 mmol) to give a crude solid which was purified directlyby column chromatography on silica gel (elution with ethylacetate/toluene followed by 90% chloroform/10% 2M NH₃ in methanol togive material which was recrystallized from ethyl acetate, methanol, andethyl ether to give 0.233 g (59%) of the title compound.

¹H NMR (DMSO-d6)

8.6 (d, 2H, J=5 Hz), 7.9 (d, 2H, J=9 Hz), 7.4 (d, 2H, J=5 Hz), 7.2 (m,4H), 6.9 (m, 3H), 5.3 (s, 2H), 4.2 (m, 4H), 3.0 (t, 2H, J=6 Hz). IR(KBr, cm⁻¹) 1603, 1501, 1264, 1249, 1172, 1005, 755. MS (ESI) m/e 420.Anal. Calcd for C₂₃H₂₁N₃O₃S: C, 65.85; H, 5.04; N, 10.02. Found C,65.82; H, 5.11; N, 10.34. M.P.=80–90° C.

Example 99 Preparation of2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-pyridine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 96, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.269 g, 0.819 mmol) and 2-bromomethyl-pyridine hydrobromide salt(0.311 g, 1.23 mmol) to give 0.146 g (42%) of the title compound.

¹H NMR (DMSO-d6)

8.6 (m, 1H), 7.9 (m, 3H), 7.5 (d, 1H, J=8 Hz), 7.4 (m, 1H), 7.2 (m, 4H),6.9 (m, 3H), 5.3 (s, 2H), 4.2 (m, 4H), 3.0 (t, 2H, J=6 Hz). IR (KBr,cm⁻¹) 1617, 1589, 1498, 1269, 1249, 1172, 1039, 753. MS (ESI) m/e 420.Anal. Calcd for C₂₃H₂₁N₃O₃S: C, 65.85; H, 5.04; N, 10.02. Found C,65.55; H, 4.88; N, 9.88. M.P.=115° C.

Example 100 Preparation of3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-pyridine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 96, from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.274 g, 0.834 mmol) and 3-bromomethyl-pyridine hydrobromide salt(0.316 g, 1.25 mmol) to give 0.177 g (50%) of the title compound.

¹H NMR (DMSO-d6)

8.7 (d, 1H, J=2 Hz), 8.6 (m, 1H), 7.9 (m, 3H), 7.4 (m, 1H), 7.2 (m, 4H),6.9 (m, 3H), 5.3 (s, 2H), 4.2 (m, 4H), 3.0 (t, 2H, J=6 Hz). IR (KBr,cm⁻¹) 1610, 1588, 1498, 1464, 1421, 1299, 1249, 1173, 1006, 758. MS(ESI) m/e 420. Anal. Calcd for C₂₃H₂₁N₃O₃S: C, 65.85; H, 5.04; N, 10.02.Found C, 65.83; H, 5.02; N, 10.04. M.P.=111–112° C.

Example 101 Preparation of{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea

a) 4-Ethoxycarbonylamino-benzoic acid methyl ester

Ethyl chloroformate (16.15 g, 148.85 mmol, 1.5 eq.) was added dropwisevia syringe to a solution of methyl 4-aminobenzoate (15.0 g, 99.23 mmol,1 eq.) in pyridine (400 mL) at 0° C. After addition was complete, thereaction was allowed to stir and gradually warm to room temperature.After 4 hours, the pyridine was removed in vacuo and the residuesuspended in water. The aqueous mixture was extracted with 50% Et2O inEtOAc. The combined organic layers were washed with aqueous 1M HCl,saturated sodium bicarbonate, and then brine, dried over MgSO4,filtered, and the solvent removed in vacuo to afford 21.79 g (98%) of4-ethoxycarbonylamino-benzoic acid methyl ester as a yellow solid.

¹H NMR (DMSO-d6) δ 10.04 (s, 1H), 7.88 (d, 2H, J=9 Hz), 7.59 (d, 2H, J=9Hz), 4.15 (q, 2H, J=7 Hz), 3.81 (s, 3H), 1.26 (t, 3H, J=7 Hz). IR (KBr,cm⁻¹) 3318, 1730, 1692, 1596, 1538, 1415, 1298, 1224, 1180, 1057. MS(ES⁺) m/e 224. MS (ES⁻) m/e 222. Anal. Calcd for C₁₁H₁₃NO₄ C, 59.19; H,5.87; N, 6.27. Found C, 59.33; H, 5.92; N, 6.30. MP 159–162° C.

b) (4-Hydrazinocarbonyl-phenyl)-carbamic acid ethyl ester

Hydrazine hydrate (3.59 g, 112.0 mmol, 5 eq.) was added to a solution of4-ethoxycarbonylamino-benzoic acid methyl ester (5.0 g, 22.40 mmol, 1eq.) in ethanol. The mixture was heated at 76° C. for 16 h. The solventwas removed in vacuo. The resultant white solid was suspended in EtOAc(150 mL) and heated on a hot plate until ˜100 mL remained, then allowedto cool. The resultant precipitate was collected by filtration to give4.25 g (85%) of (4-hydrazinocarbonyl-phenyl)-carbamic acid ethyl esteras a white solid.

¹H NMR (DMSO-d6) δ 9.85 (s, 1H), 9.56 (s, 1H), 7.74 (d, 2H, J=9 Hz),7.50 (d, 2H, J=9 Hz), 4.52 (br s, 2H), 4.13 (q, 2H, J=7 Hz), 1.25 (t,3H, J=7 Hz). IR (KBr, cm⁻¹) 3303, 3278, 1715, 1631, 1593, 1525, 1503,1328, 1228, 1067. MS (ES⁺) m/e 224. Anal. Calcd for C₁₀H₁₃N₃O₃ C, 53.81;H, 5.87; N, 18.82. Found C, 53.52; H, 5.86; N, 19.20. MP softening at186° C. then 193–195° C.

c)(4-{N′-[2-(2-Phenoxy-ethylsulfanyl)-acetyl]-hydrazinocarbonyl}-phenyl)-carbamicacid ethyl ester

EEDQ (8.30 g, 33.55 mmol, 1.1 eq.) was added as a solid to a solution of(2-Phenoxyethylthio)acetic acid (6.47 g, 30.50 mmol, 1 eq.) in anhydrous450 mL acetonitrile and 150 mL THF at room temperature. The reaction wasstirred at room temperature for 1 h, then(4-hydrazinocarbonyl-phenyl)-carbamic acid ethyl ester (7.49 g, 33.55mmol, 1.1 eq.) was added as a solid. The mixture was stirred at roomtemperature for an additional 16 h. The solvent was removed in vacuo toafford a tan solid. The solid was suspended in aqueous 1 M HCl andextracted with EtOAc. The organic extract was washed with water,saturated aqueous sodium bicarbonate, and brine, dried over magnesiumsulfate, filtered and concentrated to afford an off-white solid. Theresulting solid was recrystallized from EtOAc and collected byfiltration to afford 10.01 g (79%) of(4-{N′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazinocarbonyl}-phenyl)-carbamicacid ethyl ester as an off-white solid.

¹H NMR (DMSO-d6) δ 10.28 (s, 1H), 10.05 (s, 1H), 9.94 (s, 1H), 7.82 (d,2H, J=9 Hz), 7.55 (d, 2H, J=9 Hz), 7.29 (m, 2H), 6.95 (m, 3H), 4.16 (m,4H), 3.32 (s, 2H), 3.04 (t, 2H, J=7 Hz), 1.26 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1737, 1525, 1508, 1498, 1215. MS (ES⁺) m/e 418. MS (ES⁻)m/e 416. Anal. Calcd for C₂₀H₂₃N₃O₅S C, 57.54; H, 5.55; N, 10.06. FoundC, 57.18; H, 5.59; N, 10.10.

d){4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester

Triphenylphosphine (2.76 g, 10.54 mmol, 1.1 eq.) was added to asuspension of(4-{N′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazinocarbonyl}-phenyl)-carbamicacid ethyl ester (4.0 g, 9.58 mmol, 1 eq.) in anhydrous THF (250 mL) atroom temerature. Triethylamine (3.49 g, 34.49 mmol, 3.6 eq.) was thenadded to the mixture via syringe. After stirring for 5 minutes, carbontetrabromide (3.50 g, 10.54 mmol, 1.1 eq.) was added as a solid withvigorous stirring. The reaction was allowed to stir at room temperaturefor 16 h. The solvent was removed in vacuo leaving a dark brown solid.The solid was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase to afford 1.93 g (50%)of{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester as a yellow solid.

¹H NMR (DMSO-d6) δ 10.06 (s, 1H), 7.88 (d, 2H, J=9 Hz), 7.67 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.18 (m, 6H), 3.02 (t, 2H, J=7 Hz),1.26 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3432, 3009, 1737, 1522, 1504,1242, 1226, 1224, 1216, 1210, 1206, 1182. MS (ES⁺) m/e 400. MS (ES⁻) m/e398. Anal. Calcd for C₂₀H₂₁N₃O₄S C, 60.14; H, 5.30; N, 10.52. Found C,59.78; H, 5.34; N, 10.41.

e) Preparation of{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea

Triethylamine (0.30 g, 3.0 mmol, 1.2 eq.) was added via syringe to asuspension of{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (1.0 g, 2.5 mmol, 1 eq.) in anhydrous toluene (10 mL).The mixture was heated to reflux, after 5 minutes,B-chlorocatecholborane (0.46 g, 3.0 mmol, 1.2 eq.) was added as a solidand the reaction allowed to stir at refux for 15 minutes. The reactionwas allowed to cool to about 40° C. and then ammonia in methanol (1.07mL of 7M NH3 in MeOH) was added via syringe with vigorous stirring(turning the dark brown solution to a yellow suspension). The suspensionwas allowed to stir at room temperature for 1.5 h. The resultantsuspension was filtered to obtain 1.19 g of a yellow solid, which waspurified by recrystallization from ethanol to afford 0.67 g (72%){4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a light yellow solid.

¹H NMR (DMSO-d6) δ 8.97 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.61 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.94 (m, 3H), 6.05 (s, 2H), 4.20 (m, 4H), 3.02 (t,2H, J=7 Hz). IR (KBr, cm⁻¹) 3343, 3175, 1699, 1599, 1530, 1497, 1418,1242, 843. MS (ES⁺) m/e 371. MS (ES⁻) m/e 369. Anal. Calcd forC₁₈H₁₈N₄O₃S C, 58.36; H, 4.90; N, 15.12. Found C, 58.21; H, 4.95; N,14.96. MP>220° C.

Example 102 Preparation of1,1-dimethyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) and dimethylamine (2M in THF,1.2 mL, 2.4 mmol, 1.2 eq.) to produce 0.53 g (67%) of1,1-dimethyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas an off-white solid.

¹H NMR (DMSO-d6) δ 8.68 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.71 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.02 (t, 2H, J=7 Hz),2.95 (s, 6H). IR (CHCl₃, cm⁻¹) 3009, 1674, 1598, 1519, 1498, 1415, 1244,1173. MS (ES⁺) m/e 399. MS (ES⁻) m/e 397. Anal. Calcd for C₂₀H₂₂N₄O₃S C,60.28; H, 5.56; N, 14.06. Found C, 60.26; H, 5.47; N, 13.80. AnalyticalHPLC 97.3% purity. MP softening at 163° C. then 167–169° C.

Example 103 Preparation of pyrrolidine-1-carboxylic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) and pyrrolidine (0.17 g, 2.4mmol, 1.2 eq.) to produce 0.50 g (59%) of pyrrolidine-1-carboxylic acid{-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideas an orange/brown solid.

¹H NMR (DMSO-d6) δ 8.51 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.76 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.40 (m, 4H), 3.02 (t,2H, J=7 Hz), 1.86 (m, 4H). IR (KBr, cm⁻¹) 3394, 1660, 1595, 1524, 1497,1252, 835, 759. MS (ES⁺) m/e 425. MS (ES⁻) m/e 423. Anal. Calcd forC₂₂H₂₄N₄O₃S C, 62.24; H, 5.70; N, 13.20. Found C, 61.85; H, 5.81; N,12.93. Analytical HPLC>99% purity. MP 184–185° C.

Example 104 Preparation of piperidine-1-carboxylic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) and piperidine (0.20 g, 2.4mmol, 1.2 eq.) to produce 0.33 g (38%) of piperidine-1-carboxylic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideas a light yellow solid.

¹H NMR (DMSO-d6) δ 8.84 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.44 (m, 4H), 3.02 (t,2H, J=7 Hz), 1.54 (m, 6H). IR (CHCl₃, cm⁻¹) 3005, 2944, 2860, 1662,1599, 1515, 1497, 1420, 1312, 1241, 1181. MS (ES⁺) m/e 439. MS (ES⁻) m/e437. Anal. Calcd for C₂₃H₂₆N₄O₃S C, 62.99; H, 5.98; N, 12.78. Found C,62.59; H, 5.87; N, 12.48. Analytical HPLC 99% purity. MP softening at128° C. then 132–134° C.

Example 105 Preparation of1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureahydrochloride

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (1.00 g, 2.5 mmol, 1 eq.) andN,N-dimethylethylenediamine (0.26 g, 3.0 mmol, 1.2 eq.) to afford 0.93 g(85%) of1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas an orange oil following purification via silica gel flashchromatography using 10% 2M NH3 in methanol in chloroform as the mobilephase. The free base was converted to the hydrochloride salt by adding1.2 eq. of 4M HCl in 1,4-dioxane (0.33 mL) dropwise to an EtOAc solutionof the free base (0.48 g). The resulting white solid was quicklycollected by filtration and dried to give 0.26 g of1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureahydrochloride as a white solid.

¹H NMR (DMSO-d6) δ 10.06 (s, 1H), 9.70 (s, 1H), 7.84 (d, 2H, J=9 Hz),7.64 (d, 2H, J=9 Hz), 7.27 (m, 2H), 6.94 (m, 4H), 4.19 (m, 4H), 3.48 (m,2H), 3.18 (m, 2H), 3.02 (t, 2H, J=7 Hz), 2.82 (s, 6H). IR (CHCl₃, cm⁻¹)3302, 3000, 1695, 1602, 1545, 1499, 1318, 1233, 1181. MS (ES⁺) m/e 442.MS (ES⁻) m/e 440. Anal. Calcd for C₂₂H₂₈ClN₅O₃S C, 55.28; H, 5.90; N,14.65. Found C, 53.48; H, 5.62; N, 14.60. Analytical HPLC>99% purity.

Example 106 Preparation of1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) and1-(2-aminoethyl)pyrrolidine (0.27 g, 2.4 mmol, 1.2 eq.) to afford1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-ureaas a light brown oil following purification via silica gel flashchromatography using 10% 2M NH3 in methanol in diethyl ether as themobile phase. The free base was converted to the oxalate salt by adding1.1 eq. of oxalic acid (0.20 g) in acetone to a warm acetone solution ofthe amine. After several minutes, a tan solid formed which was collectedby filtration leaving1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-ureaoxalate as an off-white solid.

¹H NMR DMSO-d6) δ 9.63 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.65 (d, 2H, J=9Hz), 7.27 (m, 2H), 7.15 (m, 1H), 6.93 (m, 3H), 4.20 (m, 4H), 3.42 (m,2H), 3.23 (m, 6H), 3.01 (t, 2H, J=7 Hz), 1.92 (m, 4H). IR (CHCl₃, cm⁻¹)3345, 3230, 1689, 1599, 1541, 1498, 1243, 1224. MS (ES⁺) m/e 468. MS(ES⁻) m/e 466. Anal. Calcd for C₂₆H₃₁N₅O₇S C, 56.00; H, 5.60; N, 12.56.Found C, 55.52; H, 5.65; N, 12.09. Analytical HPLC 100% purity. MP111–115° C.

Example 107 Preparation of1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101 e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.70 g, 1.75 mmol, 1 eq.) and1-(2-aminoethyl)piperidine (0.27 g, 2.1 mmol, 1.2 eq.) to afford 0.79 g(94%) of1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-ureaas a yellow oil following purification via silica gel flashchromatography using 10% 2M NH3 in methanol in diethyl ether as themobile phase. The oil was triturated with diethyl ether/ethyl acetateand the resulting solid collected by filtration leaving1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea(0.50 g) as a yellow solid.

¹H NMR (DMSO-d6) δ 9.09 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.59 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 6.20 (br m, 1H), 4.20 (m, 4H), 3.20 (m,2H), 3.01 (t, 2H, J=7 Hz), 2.35 (m, 6H), 1.51 (m, 4H), 1.38 (m, 2H). IR(CHCl₃, cm⁻¹) 3418, 3358, 3008, 2942, 1690, 1602, 1499, 1244, 1180. MS(ES⁺) m/e 482. MS (ES⁻) m/e 480. Anal. Calcd for C₂₅H₃₁N₅O₃S C, 62.35;H, 6.49; N, 14.54. Found C, 62.07; H, 6.39; N, 14.33. Analytical HPLC100% purity. MP 126–128° C.

Example 108 Preparation of1-{4-[5-(4-Phenoxy-butyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) and1-(3-aminopropyl)pyrrolidine (0.31 g, 2.4 mmol, 1.2 eq.) to afford 0.64g (67%) of1-{4-[5-(4-phenoxy-butyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-ureaas a tan foam following purification via silica gel flash chromatographyusing 10% 2M NH3 in methanol in diethyl ether as the mobile phase. Thefree base was converted to the oxalate salt by adding 1.1 eq. of oxalicacid (0.13 g) in acetone to an acetone solution of the free base. Theresultant solid was collected by filtration and crystallized frommethanol to afford 0.39 g of1-{4-[5-(4-phenoxy-butyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-ureaoxalate as an off-white solid.

¹H NMR (DMSO-d6) δ 9.44 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.63 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 4H), 4.20 (m, 4H), 3.17 (m, 8H), 3.01 (t,2H, J=7 Hz), 1.92 (m, 4H), 1.81 (m, 2H). IR (KBr, cm⁻¹) 3364, 3293,3041, 2932, 2877, 1691, 1600, 1541, 1497, 1417, 1316, 1236, 1179, 843,757. MS (ES⁺) m/e 482. MS (ES⁻) m/e 480. Anal. Calcd for C₂₇H₃₃N₅O₇S C,56.73; H, 5.82; N, 12.25. Found C, 56.24; H, 6.08; N, 12.11. AnalyticalHPLC 97.8% purity. MP softening at 122° C. then 126–128° C.

Example 109 Preparation of1-(4-dimethylamino-butyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.87 g, 2.18 mmol, 1 eq.) with4-dimethylaminobutylamine (0.30 g, 2.62 mmol, 1.2 eq.) to afford 1.0 g(98%) of1-(4-dimethylamino-butyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas an orange oil following purification via silica gel flashchromatography using 10% 2M NH3 in methanol in diethyl ether as themobile phase. The free base was converted to the oxalate salt by adding1.1 eq of oxalic acid in acetone to an acetone solution of the freebase. The1-(4-dimethylamino-butyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate (0.74 g) was collected by filtration leaving a yellow solid.

¹H NMR (DMSO-d6) δ 9.54 (s, 1H), 7.81 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9Hz), 7.27 (m, 2H), 7.11 (br t, 11), 6.93 (m, 3H), 4.20 (m, 4H), 3.13 (m,2H), 3.02 (m, 4H), 2.74 (s, 6H), 1.65 (m, 2H), 1.47 (m, 2H). IR (CHCl₃,cm⁻¹) 3311, 3010, 1778, 1693, 1656, 1601, 1499, 1417, 1318, 1241, 1224,1180. MS (ES⁺) m/e 470. MS(ES⁻) m/e 468. Anal. Calcd for C₂₆H₃₃N₅O₇S C,55.80; H, 5.94; N, 12.51. Found C, 54.87; H, 5.63; N, 12.30. AnalyticalHPLC 100% purity. MP softening at 60° C. then 75–78° C.

Example 110 Preparation of1-(5-dimethylamino-pentyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) with5-(dimethylamino)pentylamine (0.31 g, 2.4 mmol, 1.2 eq.) to afford 0.92g (95%) of1-(5-dimethylamino-pentyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a dark yellow oil following purification via silica gel flashchromatography using 7.5% 2M NH3 in methanol in diethyl ether as themobile phase. The oil was converted to the oxalate salt by adding 1.1eq. of oxalic acid (0.19 g) in acetone to an acetone solution of thefree base. The solid that formed was collected by filtration to afford0.73 g of1-(5-dimethylamino-pentyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate as an off-white solid.

¹H NMR (DMSO-d6) δ 9.33 (s, 1H), 7.81 (d, 2H, J=9 Hz), 7.62 (d, 2H, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 6.79 (br t, 1H), 4.19 (m, 4H), 3.10 (m,2H), 3.01 (m, 4H), 2.73 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H), 1.31 (m,2H). IR (KBr, cm⁻¹) 3394, 2937, 1696, 1600, 1541, 1499, 1416, 1405,1318, 1233, 1179, 1083, 1032, 721. MS (ES⁺) m/e 484. MS (ES⁻) m/e 482.Anal. Calcd for C₂₇H₃₅N₅O₇S C, 56.53; H, 6.15; N, 12.21. Found C, 56.47;H, 6.21; N, 11.98. MP softening at 77° C. then 82–85° C.

Example 111 Preparation of1-(6-dimethylamino-hexyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) with6-(dimethylamino)hexylamine (0.35 g, 2.4 mmol, 1.2 eq.) to afford 0.97 g(98%) of1-(6-dimethylamino-hexyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a dark yellow oil following purification via silica gel flashchromatography using 7.5% 2M NH3 in methanol in diethyl ether as themobile phase. The oil was converted to the oxalate salt by adding 1.1eq. of oxalic acid (0.21 g) in acetone to an acetone solution of thefree base. The solid that formed was collected by filtration to afford0.94 g of1-(6-dimethylamino-hexyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate as an off-white solid. The solid was recrystallized frommethanol/acetone to give an off-white crystalline solid.

¹H NMR (DMSO-d6) δ 9.32 (s, 1H), 7.80 (d, 2H, J=9 Hz), 7.62 (d, 2, J=9Hz), 7.27 (m, 2H), 6.93 (m, 3H), 6.78 (br t, 1H), 4.20 (m, 4H), 3.09 (m,2H), 2.99 (m, 4H), 2.72 (s, 6H), 1.59 (m, 2H), 1.44 (m, 2H), 1.31 (m,4H). IR, (KBr, cm⁻¹) 3334, 3041, 2931, 2859, 1690, 1600, 1543, 1498,1244, 1179. MS (ES⁺) m/e 498. MS (ES⁻) m/e 496. Anal. Calcd forC₂₈H₃₇N₅O₇S C, 57.23; H, 6.35; N, 11.92. Found C, 56.55; H, 6.21; N,11.69. Analytical HPLC 95% purity. MP softening at 100° C. then 105–108°C.

Example 112 Preparation of1-(2-dimethylamino-ethyl)-1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) andN,N,N′-trimethylethylenediamine (0.25 g, 2.4 mmol, 1.2 eq.) to afford0.73 g (80%) of1-(2-dimethylamino-ethyl)-1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a light yellow solid following purification via silica gel flashchromatography using 10% 2M NH3 in methanol in diethyl ether as themobile phase.

¹H NMR (DMSO-d6) δ 9.63 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.62 (m, 2H),7.27 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.40 (t, 2H, J=7 Hz), 3.02 (t,2H, J=7 Hz), 2.95 (s, 3H), 2.45 (m, 2H), 2.24 (s, 61). IR (CHCl₃, cm⁻¹)3008, 2953, 2862, 2791, 1674, 1603, 1542, 1499, 1470, 1390, 1317, 1243,1180. MS (ES⁺) m/e 456. MS (ES⁻) m/e 454. Anal. Calcd for C₂₃H₂₉N₅O₃S C,60.64; H, 6.42; N, 15.37. Found C, 60.34; H, 6.29; N, 15.17. AnalyticalHPLC 99% purity. MP softening at 121° C. then 134–135° C.

Example 113 Preparation of1-benzyl-1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) andN′-benzyl-N,N-dimethylethylenediamine (0.43 g, 2.4 mmol, 1.2 eq.) toafford 0.89 g (84%)1-benzyl-1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a yellow oil following purification via silica gel flashchromatography using 5% 2M NH3 in methanol in diethyl ether as themobile phase. The free base was converted to the oxalate salt by adding1.2 eq. of oxalic acid (0.18 g) in acetone to an acetone solution of thefree base. Addition of diethyl ether to the cloud point and coolingproduced 0.98 g of1-benzyl-1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate as an off-white solid.

¹H NMR (DMSO-d6) δ 9.43 (s, 1H), 7.86 (d, 2H J=9 Hz), 7.73 (d, 2H, J=9Hz), 7.38 (m, 2H), 7.28 (m, 5H), 6.93 (m, 3H), 4.69 (m, 2H), 4.19 (m,4H), 3.58 (m, 2H), 3.09 (m, 2H), 3.02 (t, 2H, J=7 Hz), 2.69 (s, 6H). IR(CHCl₃, cm⁻¹) 3306, 3009, 1777, 1661, 1601, 1499, 1316, 1242, 1224. MS(ES⁺) m/e 532. MS(ES⁻) m/e 530. Anal. Calcd for C₃₁H₃₅N₅O₇S C, 59.89; H,5.67; N, 11.26. Found C, 58.66; H, 5.32; N, 11.23. Analytical HPLC 98%purity. MP softening at 70° C. then 72–76° C.

Example 114 Preparation of1-(3-dimethylamino-propyl)-1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-urea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e, from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) andN,N,N′-trimethyl-1,3-propanediamine (0.24 g, 2.1 mmol, 1.2 eq.). toafford 0.51 g (62%) of1-(3-dimethylamino-propyl)-1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas a crystalline orange solid following purification by silica gel flashchromatography using 10% 2M NH3 in methanol in chloroform as the mobilephase and recrystallization from EtOAc/Et2O.

¹H NMR (DMSO-d6) δ 9.66 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.62 (m, 2H),7.27 (M, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.32 (m, 2H), 3.02 (t, 2H, J=7Hz), 2.89 (s, 3H), 2.29 (m, 2H), 2.23 (s, 6H), 1.70 (m, 2H). IR (CHCl₃,cm⁻¹) 3008, 2950, 2827, 2787, 1665, 1604, 1498, 1229, 1179. MS (ES⁺) m/e470. MS (ES⁻) m/e 468. Anal. Calcd for C₂₄H₃₁N₅O₃S C, 61.38; H, 6.65; N,14.91. Found C, 60.75; H, 6.49; N, 14.43. Analytical HPLC 99% yield. MPsoftening at 114° C. then transition at 116–118° C. then melting at136–139° C.

Example 115 Preparation of1-benzyl-1-(3-dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-carbamicacid ethyl ester (0.80 g, 2.0 mmol, 1 eq.) andN′-Benzyl-N,N-dimethyl-propane-1,3-diamine (0.46 g, 2.4 mmol, 1.2 eq.)to afford 0.80 g (73%) of1-benzyl-1-(3-dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaas an orange oil following purification by silica gel flashchromatography using 5% 2M NH3 in methanol in chloroform as the mobilephase. The free base was converted to the oxalate salt by adding 1.2 eq.of oxalic acid (0.14 g) in acetone to an acetone solution of the freebase. Addition of diethyl ether to the resulting yellow solution andcooling produced 0.62 g of1-benzyl-1-(3-dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-ureaoxalate as a tan solid.

¹H NMR (DMSO-d6) δ 9.03 (s, 1H), 7.85 (d, 2H, J=9 Hz), 7.75 (d, 2H, J=9Hz), 7.37 (m, 2H), 7.27 (m, 5H), 6.93 (m, 3H), 4.66 (m, 2H), 4.19 (m,4H), 3.37 (m, 2H), 3.00 (m, 4H), 2.69 (s, 6H), 1.88 (m, 2H). IR (KBr,cm⁻¹) 3435, 1723, 1653, 1599, 1524, 1498, 1234, 838, 703. MS (ES⁺) 546.MS (ES⁻) m/e 544. Anal. Calcd for C₃₂H₃₇N₅O₇S C, 60.46; H, 5.87; N,11.02. Found C, 60.14; H, 5.60; N, 10.60. Analytical HPLC 99% purity. MPsoftening at 117° C. then 159–164° C.

Example 116 Preparation of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamine

a) 4-Amino-benzoic acid hydrazide

A solution of methyl 4-aminobenzoate (10 g, 66.15 mmol, 1 eq.) andhydrazine hydrate (40 mL) in absolute ethanol (120 mL) was allowed toreflux for 16 h. The solvent was removed in vacuo and the resultingoff-white solid was triturated with hot ethyl acetate. The solid wascollected by filtration to afford 9.1 g (91%) of 4-amino-benzoic acidhydrazide as an off-white solid.

¹H NMR (DMSO-d6) δ 9.25 (s, 1H), 7.53 (d, 2H, J=9 Hz), 6.52 (d, 2H, J=9Hz), 5.56 (s, 2H), 4.32 (s, 2H). IR (KBr, cm−1) 3428, 3348, 3308, 3233,1630, 1604, 1504, 1321, 1306, 958, 842. MS (ES+) m/e 152. MS (ES−) m/e150. Anal. Calcd for C₇H₉N₃O C, 55.62; H, 6.00; N, 27.80. Found C,55.93; H, 6.21; N, 27.53.

b) 4-Amino-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

The above compound was prepared in a manner similar to that exemplified.for the preparation of Example 101c, from (2-phenoxyethylthio)aceticacid (4.25 g, 20.0 mmol, 1 eq.) and 4-amino-benzoic acid hydrazide (3.33g, 22.0 mmol, 1.1 eq.) to afford 5.85 g (85%) of 4-amino-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide as a yellow foamfollowing purification by silica gel flash chromatography using a stepgradient of acetone in hexane as the mobile phase.

¹H NMR (DMSO-d6) δ 9.91 (s, 2H), 7.60 (d, 2H, J=9 Hz), 7.28 (m, 2H),6.95 (m, 3H), 6.55 (d, 2H, J=9 Hz), 4.19 (t, 2H, J=7 Hz), 3.31 (s, 2H),3.03 (t, 2H, J=9 Hz). IR (KBr, cm⁻¹) 3450, 3357, 3268, 3214, 1696, 1627,1611, 1592, 1562, 1482, 1291, 1242, 1173, 837. MS (ES⁺) m/e 346. MS(ES⁻) m/e 344. Anal. Calcd for C₁₇H₁₉N₃O₃S C, 59.11; H, 5.54; N, 12.16.Found C, 59.13; H, 5.79; N, 12.09.

c)4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101d, from 4-amino-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (11.42 g, 33.06 mmol)to afford 10.77 g (99%) of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamineas a yellow solid following purification by silica gel flashchromatography using a step gradient of ethyl acetate in hexane as themobile phase.

¹H NMR (DMSO-d6) δ 7.60 (d, 2H, J=9 Hz), 7.27 (m, 2H), 6.93 (m, 3H),6.66 (d, 2H, J=9 Hz), 5.93 (m, 2H), 4.18 (m, 4H), 3.00 (t, 2H, J=7 Hz).IR (CHCl₃, cm⁻¹) 3011, 1624, 1610, 1501, 1243, 1180. MS (ES+) m/e 328.Anal. Calcd for C₁₇H₁₇N₃O₂S C, 62.37; H, 5.23; N, 12.83. Found C, 61.61;H, 5.12; N, 12.50. Analytical HPLC 97.8% purity. MP 126–130° C.

Example 117 Preparation of1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiourea

A solution of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamine(5.21 g, 15.92 mmol, 1 eq., prepared in Example 119) in anhydrousacetonitrile was treated with 1,1′-thiocarbonyldiimidazole (3.15 g,15.92 mmol, 1 eq.) as a solid and stirred at room temperature for 16 h.The solvent was removed in vacuo leaving imidazole-1-carbothioic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideas a brown oil. A portion of one-half of this material (7.96 mmol) wasdissolved in anhydrous DMP and treated with N,N-dimethylethylenediamine(0.84 g, 9.55 mmol, 1.2 eq.). The resulting mixture was heated at 100°C. for 1.5 h, cooled, then diluted with EtOAc and washed with 50% brine.The organic layer was collected, dried over MgSO4, filtered, and thesolvent removed in vacuo leaving a yellow oil. The residue was purifiedby preparative HPLC to afford 2.33 g (64%) of1-(2-dimethylamino-ethyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thioureaas a yellow oil which later crystallized. A portion of material wasrecrystallized from ethyl acetate to afford an off-white solid.

¹H NMR (DMSO-d6) δ 10.06 (s, 1H), 7.84 (m, 5H), 7.27 (m, 2H), 6.93 (m,3H), 4.20 (m, 4H), 3.56 (m, 2H), 3.02 (t, 2H, J=7 Hz), 2.45 (m, 2H),2.20 (s, 6H). IR (CHCl₃, cm⁻¹) 3429, 3407, 3007, 2982, 2956, 2829, 2781,1731, 1614, 1601, 1497, 1337, 1243, 1173. MS (ES⁺) m/e 458. MS (ES⁻) m/e456 Anal. Calcd for C₂₂H₂₇N₅O₂S₂ C, 57.74; H, 5.95; N, 15.30. Found C,57.60; H, 5.88; N, 14.89. Analytical HPLC 96.9% purity. MP 155–158° C.

Example 118 Preparation of1-(3-dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiourea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 117, from{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide(7.96 mmol, 1 eq) and 3-dimethylaminopropylamine (0.98 g, 9.55 mmol, 1.2eq.) to afford 2.87 g (77%) of1-(3-dimethylamino-propyl)-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thioureaas a yellow oil which started to crystallize following purification bypreparative HPLC. A small portion was recrystallized from ethyl acetategiving an off-white solid.

¹H NMR (DMSO-d6) δ 9.86 (s, 1H), 8.25 (s, 1H), 7.89 (d, 2H, J=9 Hz),7.70 (d, 2H, J=9 Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.50 (m,2H), 3.02 (t, 2H, J=7 Hz), 2.21 (t, 2H, J=7 Hz), 2.10 (s, 6H), 1.68 (m,2H). IR (CHCl₃, cm⁻¹) 3411, 2980, 2952, 2862, 2827, 2787, 1615, 1601,1588, 1532, 1499, 1469, 1307, 1242. MS (ES⁺) m/e 472.

MS (ES⁻) m/e 470. Anal. Calcd for C₂₃H₂₉N₅O₂S₂ C, 58.57; H, 6.20; N,14.85. Found C, 59.11; H, 6.49; N, 14.85. Analytical HPLC 97.9% purity.MP 136–139° C.

Example 119 Preparation ofN-(2-dimethylamino-ethyl)-N′-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineoxalate

Diphenyl cyanocarbonimidate (1.53 g, 6.42 mmol, 1.05 eq.) was added to ayellow solution of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamine(2.0 g, 6.11 mmol, 1 eq., prepared in Example 116) in 50 mL of anhydrousacetonitrile. The resultant solution heated at reflux for 16 h. Thesolvent was removed in vacuo to afford a yellow oil that solidified onstanding. The solid was triturated with diethyl ether to afford thecorresponding carbamimidic acid phenyl ester (1.78 g, 62% yield) as ayellow solid (MS for carbamimidic acid phenyl ester (ES⁻) m/e 470).N,N-dimethylethylenediamine (1.87 g, 21.2 mmol, 20 eq.) was added to asolution of this carbamimidic acid phenyl ester (0.50 g, 1.06 mmol, 1eq.) in isopropanol, then heated to reflux. After 5 h, the reaction wascooled, diluted with ethyl acetate, and washed with aqueous sodiumbicarbonate. The organic layer was collected, dried over MgSO4,filtered, and the solvent removed in vacuo to afford an orange oil. Theoil was purified by silica gel flash chromatography using 10% 2M NH3 inmethanol in diethyl ether as the mobile phase to afford 0.14 g (29%) ofN-(2-dimethylamino-ethyl)-N-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineas an off-white solid. The free base was converted to the oxalate saltby adding 1.1 eq. of oxalic acid (0.03 g) in acetone to an acetonesolution of the base to afford 0.13 g ofN-(2-dimethylamino-ethyl)-N′-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineoxalate as a tan solid.

¹H NMR (DMSO-d6) δ 10.04 (s, 1H), 7.93 (m, 3H), 7.48 (d, 2H, J=9 Hz),7.27 (m, 2H), 6.93 (m, 3H), 4.19 (m, 4H), 3.02 (m, 4H), 2.81 (t, 2H, J=7Hz), 2.73 (s, 6H). IR (KBr, cm⁻¹) 3404, 3302, 3040, 2174, 1720, 1618,1598, 1562, 1500, 1461, 1243, 1010. MS (ES⁺) m/e 466. MS (ES⁻) m/e 464.Anal. Calcd for C₂₅H₂₉N₇O₆S C, 54.04; H, 5.26; N, 17.65. Found C, 51.71;H, 5.70; N, 14.23. Analytical HPLC 95.7% purity. MP softening at 138° C.then decomposition at 145–147° C.

Example 120 Preparation ofN-(3-dimethylamino-propyl)-N′-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 119, from the carbamimidic acid phenylester (1.2 g, 2.54 mmol, 1 eq.) and 3-dimethylaminopropylamine (5.19 g,50.8 mmol, 20 eq.) to afford 0.22 g (18%) ofN-(3-dimethylamino-propyl)-N′-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineas an off-white solid. The free base was converted to the oxalate saltas described to afford 0.20 g ofN-(3-dimethylamino-propyl)-N′-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-cyanoguanidineoxalate as a white solid.

¹H NMR (DMSO-d6) δ 9.78 (s, 1H), 7.92 (m, 3H), 7.47 (d, 2H, J=9 Hz),7.28 (m, 2H), 6.93 (m, 3H), 4.20 (m, 4H), 3.33 (m, 2H), 3.02 (m, 4H),2.73 (s, 6H), 1.88 (m, 2H). IR (KBr, cm⁻¹) 3316, 3255, 2171, 1720, 1600,1500, 1237, 755,720. MS (ES⁺) m/e 480. MS (ES⁻) m/e 478. Anal. Calcd forC₂₆H₃₁N₇O₆S C, 54.82; H, 5.49; N, 17.21. Found C, 53.91; H, 5.43; N,16.76. Analytical HPLC 100% purity. MP softening at 110° C. thendecomposition from 130–134° C.

Example 121 Preparation of 2-piperidin-1-yl-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideoxalate

a) Preparation of 2-chloro-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

A solution of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenylamine(3.0 g, 9.16 mmol, 1 eq.) in anhydrous CH₂Cl₂ was treated withtriethylamine (1.39 g, 13.74 mmol, 1.5 eq.) and2-chloro-1-ethanesulfonyl chloride (1.79 g, 10.99 mmol, 1.2 eq.). Thereaction was allowed to stir at room temperature for 16 h, then wasquenched with water and the organic layer removed. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO4, filtered, and concentrated to afford an orangeoil. The oil was purified by silica gel flash chromatography using astep gradient of ethyl acetate in hexane as the mobile phase to afford0.97 g (23%) of 2-chloro-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideas an off-white solid.

¹H NMR (DMSO-d6) δ 8.06 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=9 Hz), 7.28 (m,3H), 6.91 (m, 3H), 6.44 and 6.41 (m, 2H total), 6.32 and 6.27 (m, 2Htotal), 4.25 (s, 2H), 4.18 (t, 2H, J=7 Hz), 3.03 (t, 2H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1602, 1491, 1384, 1217, 1163, 916. MS (ES⁻) m/e 416[M-Cl]⁻. Anal. Calcd for C₁₉H₂₀ClN₃O₄S C, 4.44; N, 9.26. Found C, 49.71;H, 4.15; N, 8.27.

b) Preparation of 2-piperidin-1-yl-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideoxalate

2-Chloro-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide(0.91 g, 2.0 mmol, 1 eq.) in anhydrous DMF was treated with sodiumbicarbonate (0.50 g, 6.0 mmol, 3 eq.) and sodium iodide (0.03 g, 0.2mmol, 0.1 eq.) followed by piperidine (0.51 g, 6.0 mmol, 3 eq.). Thereaction was then heated to 90° C. and allowed to stir at thattemperature for 16 h. The reaction was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with waterand brine, dried over MgSO4, filtered, and the solvent removed in vacuoleaving an orange oil which was purified by silica gel flashchromatography using 10% 2M NH3 in methanol in diethyl ether as themobile phase to afford 0.95 g (94%) of 2-piperidin-1-yl-ethanesulfonicacid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideas a yellow oil. The free base was converted to the oxalate salt byadding 1.1 eq. of oxalic acid (0.19 g) in acetone dropwise to an acetonesolution of the free base. The resulting white precipitate was collectedby filtration and crystallized from methanol to afford 0.48 g of2-piperidin-1-yl-ethanesulfonic acid{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amideoxalate as a crystalline white solid.

¹H NMR (DMSO-d6) δ 7.93 (d, 2H, J=9 Hz), 7.39 (d, 2H, J=9 Hz), 7.27 (m,2H), 6.93 (m, 3H), 4.19 (m, 4H), 3.62 (m, 2H), 3.14 (m, 2H), 3.02 (t,2H, J=7 Hz), 2.82 (m, 4H), 1.57 (m, 4H), 1.41 (m, 2H). IR (KBr, cm−1)3409, 1617, 1344, 1243, 1159, 916, 759, 705. MS (ES⁺) m/e 503. MS (ES⁻)m/e 501. Anal. Calcd for C₂₆H₃₂N₄O₈S₂ C, 52.69; H, 5.44; N, 9.45. FoundC, 52.44; H, 5.46; N, 9.37. Analytical HPLC 99.6% purity. MP softeningat 159° C. then 162–166° C.

Example 122 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[((2-(N-methylpyrrolidin-2-yl)ethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazole

a)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(methoxycarbonyl)phenyl]-1,3,4-oxadiazole

A solution of 2-[(2-phenoxyethyl)thio]acetic acid hydrazidehydrochloride (3.15 g, 12 mmol), triethylamine (4.2 mL, 30 mmol) andterephthalic acid monomethyl ester chloride (1.99 g, 10 mmol) inmethylene chloride (100 mL) was stirred at room temperature for 3 h.After filtering the solids, the filtrate was concentrated. The residuewas recrystallized from ethanol to yield a pale yellow solid (1.31 g,3.37 mmol). This solid, 4-(dimethylamino)phenyldiphenylphosphine (2.06g, 6.74 mmol), triethylamine (1.4 mL, 10 mmol) and carbon tetrachloride(1.6 mL, 16.6 mmol) were stirred in acetonitrile (75 mL) at roomtemperature for 18 h. The product was filtered from the reactionmixture, washed with acetonitrile (50 mL) and dried to yield 1.13 g(30%) of a pale yellow solid, which was used without furtherpurification.

¹H NMR (CDCl₃) δ 8.14 (d, 2H, J=9 Hz), 8.06 (d, 2H, J=9 Hz), 7.23 (m,2H), 6.92 (dd, 1H, J=7 and 8 Hz), 6.86 (d, 2H, J=8 Hz), 4.19 (t, 2H,J=12 Hz), 4.05 (s, 2H), 3.93 (s, 3H), 3.03 (t, 2H, J=12 Hz). MS (ES+)m/e 371 (M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(hydroxycarbonyl)phenyl]-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(methoxycarbonyl)phenyl]-1,3,4-oxadiazole(1.13 g, 3.0 mmol) and 2N aqueous NaOH (4.5 mL, 9.0 mmol) in THF (20 mL)was stirred at room temperature for 16 h. The mixture was diluted withwater (30 mL) and extracted with ethyl ether (50 mL). The aqueousmaterial was acidified with 2N HCl to a pH of 5, then extracted withethyl ether (3×30 mL). The organic material was dried (MgSo₄), filteredand concentrated to yield 803 mg (74%) of a pale yellow solid.

¹H NMR (CDCl₃) δ 8.20 (d, 2H, J=8 Hz), 8.12 (d, 2H, J=8 Hz), 7.25 (m,2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz), 4.20 (t, 2H,J=12 Hz), 4.08 (s, 2H), 3.05 (t, 2H, J=12 Hz). MS (ES−) m/e 355 (M−1).

c)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[((2-(N-methylpyrrolidin-2-yl)ethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(hydroxycarbonyl)phenyl]-1,3,4-oxadiazole(300 mg, 0.84 mmol), 2-(2-aminoethyl)-1-methylpyrrolidine (0.18 mL, 1.24mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(242 mg, 1.26 mmol) and 1-hydroxybenzo-triazole (171 mg, 1.26 mmol) inN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h.The mixture was diluted with ethyl acetate (50 mL) and extracted withsaturated aqueous lithium chloride (2×25 mL), dried (MgSO₄), filteredand concentrated to yield 700 mg of a yellow oil. This oil was purifiedby preparative TLC [90% methylend chloride-5% methanol-5% (2.0 N ammoniain methanol)] to yield 146 mg (37%) of a white solid.

¹H NMR (CDCl₃) δ 8.75 (br s, 1H), 8.07 (d, 2H, J=8 Hz), 7.88 (d, 2H, J=8Hz), 7.24 (m, 2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz),4.19 (t, 2H, J=12 Hz), 4.05 (s, 2H), 3.77 (m, 1H), 3.47 (m, 1H), 3.15(m, 1H), 3.04 (t, 2H, J=12 Hz), 2.57 (m, 1H), 2.40 (s, 3H), 2.31 (m,1H), 1.90 (m, 2H), 1.75 (m, 4H). IR (film, cm⁻¹) 3432, 3335, 2943, 2868,2778, 2359, 1641, 1584, 1547, 1493, 1456, 1302, 1244, 1082, 1021, 863,753, 694, 654. MS (ES+) m/e 467 (M+1). Anal. Calcd for C₃₁H₃₃N₃O₂S: C,64.35; H, 6.48; N, 12.01; S, 6.87. Found C, 64.42; H, 6.19; N, 12.45; S,6.80.

Example 123 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[((2-piperidinoethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazole

This compound was synthesized similarly to2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[((2-(N-methylpyrrolidin-2-yl)ethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazole using1-(2-aminoethyl)piperidine (0.12 mL).

¹H NMR (CDCl₃) δ 8.08 (d, 2H, J=9 Hz), 7.89 (d, 2H, J=9 Hz), 7.24 (m,2H), 7.15 (br s, 1H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=9 Hz),4.20 (t, 2H, J=12 Hz), 4.06 (s, 2H), 3.53 (dd, 2H, J=6 and 11 Hz), 3.04(t, 2H, J=12 Hz), 2.57 (dd, 2H, J=6 and 11 Hz), 2.44 (m, 4H), 1.60 (m,4H), 1.47 (m, 2H). IR (film, cm⁻¹) 3313, 2938, 2885, 2851, 2778, 1635,1552, 1493, 1296, 1239, 1024, 747. MS (ES+) m/e 467 (+1). Anal. Calcdfor C₂₅H₃₀N₄O₃S: C, 64.35; H, 6.48; N, 12.01; S, 6.87. Found C, 64.02;H, 6.41; N, 12.00; S, 7.02.

Example 124 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N′,N′-dimethyl-1,3-propanediamino)carbonyl]phenyl}-1,3,4-oxadiazole

This compound was synthesized similarly to2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[((2-(N-methylpyrrolidin-2-yl)ethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazoleusing 3-(dimethylamino)propylamine (0.11 mL).

¹H NMR (CDCl₃) δ 8.81 (br s, 1H), 8.07 (d, 2H, J=8 Hz), 7.87 (d, 2H, J=8Hz), 7.24 (m, 2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz),4.20 (t, 2H, J=12 Hz), 4.05 (s, 2H), 3.58 (dd, 2H, J=6 and 11 Hz), 3.04(t, 2H, J=12 Hz), 2.54 (dd, 2H, J=6 and 11 Hz), 2.30 (s, 6H), 1.77 (m,2H). IR (film, cm⁻¹) 3431, 3345, 2943, 2867, 2810, 2762, 1641, 1581,1542, 1494, 1466, 1300, 1246, 1178, 1082, 1026, 750, 693, 651. MS (ES+)m/e 441 (M+1). Anal. Calcd for C₂₃H₂₈N₄O₃S: C, 62.70; H, 6.41; N, 12.72;S, 7.28. Found C, 62.13; H, 6.32; N, 12.63; S, 6.99.

Example 125 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamino)penten-1-yl]phenyl}-1,3,4-oxadiazole,(E)- and (Z)-isomers

a) Methyl 4-(5-bromopenten-1-yl)benzoate

A mixture of methyl 4-formylbenzoate (9.85 g, 60 mmol),4-bromobutyltriphenylphosphonium bromide (31.56 g, 66 mmol), powderedNaOH (3 g, 75 mmol), and 12 drops of water in methylene chloride (150mL) was stirred under reflux for 4 h. The mixture was allowed to cool toroom temperature and filtered. The filtrate was concentrated andchromatographed on a silica gel column, eluted with ethylacetate/hexanes 1:50 to 1:30, to give the Z-isomer (colorless oil, 3.68g, 22%), a mixture of Z- and E-isomers (colorless oil, 2.69 g, 16%), andthe E-isomer (white solid, 2.97 g, 17%).

E-isomer: ¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8.5 Hz), 7.37 (d, 2H, J=8.4Hz), 6.46 (d, 1H, J=15.8 Hz), 6.28 (dt, 1H, J=15.8, 7.0 Hz), 3.88 (s,3H), 3.44 (t, 2H, J=6.6 Hz), 2.39 (q, 2H, J=7.0 Hz), 2.03 (quint, 2H 6.6Hz). MS (ES+) m/e 284 (M+1). Z-isomer: ¹H NMR (CDCl₃) δ 7.98 (d, 2H,J=8.1 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.48 (d, 1H, J=11.7 Hz), 5.70 (dt,1H, J=11.7, 7.3 Hz), 3.89 (s, 3H), 3.39 (t, 2H, J=6.8 Hz), 2.47 (q, 2H,J=7.3 Hz), 1.99 (quint, 2H, 6.9 Hz). MS (ES+) m/e 284 (M+1).

b) 4-(5-bromopenten-1-yl)benzoic acid

Methyl 4-(5-bromopenten-1-yl)benzoate (1.415 g, 5 mmol) was dissolved in1,4-dioxane (25 mL) and 2 N NaOH (25 mL, 50 mmol) was added. The mixturewas stirred at room temperature for 5 h, cooled in an ice bath,acidified with conc. HCl, and extracted with ether (3×25 mL). Thecombined ether extracts were dried (MgSO₄) and concentrated to give awhite solid (1.264, 94%).

E-isomer: ¹H NMR (CDCl₃) δ 8.05 (d, 2H, J=7.7 Hz), 7.43 (d, 2H, J=8.5Hz), 6.51 (d, 1H, J=16.3 Hz), 6.34 (dt, 1H, J=16.3, 6.9 Hz), 3.47 (t,2H, J=6.9 Hz), 2.43 (q, 2H, J=6.9 Hz), 2.07 (quint, 2H, 6.8 Hz). MS(ES−) m/e 268 (M−1).

c)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole

A stirred mixture of 4(5-bromopenten-1-yl)benzoic acid (1.264 g, 4.7mmol), 2-(2-phenoxyethyl)thioacetylhydrazide hydrochloride (1.314 g, 5mmol), and 4-(N,N-dimethylamino)phenyldiphenylphosphine (4.58 g, 15mmol) in acetonitrile (50 mL) was cooled in ice bath and triethylamine(3.04 g, 30 mmol) in carbon tetrachloride (3.85 g, 25 mmol) was addeddropwise. The cooling bath was removed after 10 min and stirring wascontinued for 5 h. The mixture was concentrated to approximately halfthe original volume and partitioned between ether (150 mL) and 2 N HCl(150 mL). The ether layer was washed with 2 N HCl (4×50 mL), dried(MgSO₄), and concentrated. The residue was purified by chromatography(SiO₂, ethyl acetate/hexanes 1:5) to give a white solid (1.43 g, 66%).

E-isomer: ¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.5 Hz), 7.45 (d, 2H, J=8.5Hz), 7.27 (m, 2H), 6.96 (t, 1H, J=7.7 Hz), 6.90 (d, 2H, J=8.5 Hz), 6.50(d, 1H, J=16.2 Hz), 6.32 (dt, 1H, J=16.2, 6.9 Hz), 4.22 (t, 2H, J=6.0Hz), 4.06 (s, 2H), 3.47 (t, 2H, J=6.9 Hz), 3.06 (t, 2H, J=6.0 Hz), 2.43(q, 2H, J=6.9 Hz), 2.07 (quint, 2H, 6.9 Hz). MS (ES+) m/e 460 (M+1).

Z-isomer: ¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8.5 Hz), 7.37 (d, 2H, J=8.5Hz), 7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz),6.48 (d, 1H, J=11.8 Hz), 5.72 (dt, 1H, J=11.7, 7.3 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.04 (s, 2H), 3.41 (t, 2H, J=6.6 Hz), 3.04 (t, 2H, J=6.2 Hz),2.49 (q, 2H, J=7.3 Hz), 2.01 (quint, 2H, 7.0 Hz). MS (ES+) m/e 460(M+1).

d)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamino)penten-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole(300 mg, 0.65 mmol), 2 N dimethylamine in tetrahydrofuran (1.7 mL, 3.4mmol), and potassium carbonate (903 mg, 6.5 mmol) in acetonitrile (5 mL)was stirred at room temperature for 24 h, diluted with methylenechloride (25 mL) and filtered. The filtrate was concentrated andpurified by chromatography (silica gel, methanol/methylene chloride 2%to 10%) to give a white solid (263 mg, 96%).

E-isomer: ¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.5 Hz), 7.42 (d, 2H, J=8.4Hz), 7.22˜7.27 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz),6.42 (d, 1H, J=16.1 Hz), 6.34 (dt, 1H, J=15.7, 6.4 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.40 (m, 2H), 2.30 (s,6H), 2.27 (m, 2H), 1.71 (quint, 2×17.3 Hz). IR (KBr, cm⁻¹) 3074, 3056,3038, 2955, 2924, 2856, 1602, 1495, 1237, 1168, 751. MS (ES+) m/e 424(M+1). Anal. Calcd for C₂₄H₂₉N₃O₂S: C, 68.05; H, 6.90; N, 9.92; S, 7.57.Found C, 68.16; H, 6.99; N, 10.23; S, 7.66.

Z-isomer: ¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=8.4Hz), 7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.0 Hz),6.44 (d, 1H, J=11.8 Hz), 5.75 (dt, 1H, J=11.4, 7.3 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=6.2 Hz), 2.32˜2.39 (m, 4H), 2.29(s, 6H), 1.69 (quint, 2H, 7.3 Hz). IR (KBr, cm⁻¹) 3029, 2940, 2863,2844, 2649, 1598, 1505, 1246, 1174, 752. MS (ES+) m/e 424 (M+1). Anal.Calcd for C₂₄H₂₉N₃O₂S: C, 68.05; H, 6.90; N, 9.92; S, 7.57. Found C,68.45; H, 6.44; N, 10.37; S, 7.41.

Example 126 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-pyrrolidinopenten-1-yl)phenyl]-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole(150 mg, 0.33 mmol), pyrrolidine (118 mg, 1.65 mmol), and potassiumcarbonate (457 mg, 3.3 mmol) in acetonitrile (3.5 mL) was stirred atroom temperature for 24 h, diluted with methylene chloride (15 mL),filtered, dried (MgSO₄), and concentrated. The residue was purified bypreparative TLC (silica gel, 10% methanol/methylene chloride) to give ayellow oil (129 mg, 87%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, J=8.4 Hz),7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.7 Hz), 6.87 (d, 2H, J=7.7 Hz), 6.41(d, 1H, J=15.7 Hz), 6.36 (dt, 1H, J=15.7, 6.5 Hz), 4.19 (t, 2H, J=6.2Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.46˜2.50 (m, 6H), 2.27 (q,2H, J=6.9 Hz), 1.67˜1.80 (m, 6H). IR (film, cm⁻¹) 3070, 3024, 2968,2841, 2793, 1598, 1506, 1337, 1306, 1229, 1020, 736. MS (ES+) m/e 450(M+1). Anal. Calcd for C₂₆H₃₁N₃O₂S: C, 69.46; H, 6.95; N, 9.35; S, 7.13.Found C, 68.98; H, 7.01; N, 9.73; S, 7.19.

Example 127 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-piperidinopenten-1-yl)phenyl]-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole(150 mg, 0.33 mmol), piperidine (140 mg, 1.65 mmol), and potassiumcarbonate (458 mg, 3.3 mmol) in acetonitrile (3.5 mL) was stirred atroom temperature for 18 h, diluted with methylene chloride (15 mL),filtered, dried (MgSO₄), and concentrated. The residue was purified bypreparative TLC (silica gel, 10% methanol/methylene chloride) to giveyellow oil (136 mg, 89%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.5 Hz), 7.42 (d, 2H, J=8.4 Hz),7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.4 Hz), 6.41(d, 1H, J=16.1 Hz), 6.34 (dt, 1H, J=16.1, 6.9 Hz), 4.19 (t, 2H, J=6.2Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.38˜2.43 (m, 6H), 2.25 (q,2H, J=6.9 Hz), 1.43˜1.74 (m, 8H). R (film, cm⁻¹) 3072, 3027, 2945, 2936,2691, 1600, 1533, 1274, 1196, 1020, 764. MS (ES+) m/e 464 (M+1). Anal.Calcd for C₂₇H₃₃N₃O₂S: C, 69.95; H, 7.17; N, 9.06; S, 6.92. Found C,69.24; H, 7.12; N, 9.68; S, 7.11.

Example 128 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamino)pentan-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of (E)- and(Z)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamio)penten-1-yl]phenyl}-1,3,4-oxadiazolewas made according to the above procedure from 460 mg (1 mmol) of amixture of (E)- and(Z)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole.Without purification this material was stirred withp-toluenesulfonylhydrazide (2.25 g, 12 mmol) and sodium acetatetrihydrate (1.02 g, 7.5 mmol) in tetrahydrofuran (12 mL) and water (12mL) under reflux for 6 h. 2 N NaOH (20 mL) was added and the mixture wasextracted with methylene chloride (2×20 mL). The combined methylenechloride extracts were dried (MgSO₄), and concentrated. The residue waspurified by column chromatography (silica gel, methanol/methylenechloride 2% to 5% to 10%) to give a colorless oil (333 mg, 78% over twosteps).

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=8.1 Hz), 7.27 (d, 2H, J=8.4 Hz),7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.5 Hz), 4.18(t, 2H, J=6.2 Hz), 4.02 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.66 (t, 2H,J=7.7 Hz), 2.24 (t, 2H, J=7.5 Hz), 2.20 (s, 6H), 1.65 (quint, 2H, 7.7Hz), 1.49 (q, 2H, J=7.5 Hz), 1.34 (q, 2H, J=7.5 Hz). IR (film, cm⁻¹)3034, 3017, 2954, 2883, 2820, 1515, 1357, 1344, 1235, 1137, 1002. MS(ES+) m/e 426 (M+1). Anal. Calcd for C₂₄H₃₁N₃O₂S: C, 67.73; H, 7.34; N,9.87; S, 7.53. Found C, 67.37; H, 7.42; N, 10.06; S, 7.27.

Example 129 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[6-(,N-dimethylamino)hexen-1-yl]phenyl}-3-1,3,4-oxadiazole

a)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-cyanopenten-1-yl)phenyl]-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-bromopenten-1-yl)phenyl]-1,3,4-oxadiazole(460 mg, 1 mmol) and potassium cyanide (195 mg, 3 mmol) indimethylsulfoxide (6 mL) was stirred at room temperature for 4 h. Water(25 mL) was added and the mixture was extracted with ethyl acetate (3×15mL). The combined ethyl acetate extracts were washed with water (3×15mL) and brine (15 mL), dried (MgSO₄), and concentrated to give a paleyellow solid (403 mg, 100%).

E-isomer: ¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=7.7 Hz), 7.46 (d, 2H, J=7.7Hz), 7.28 (m, 2H), 6.96 (t, 1H, J=7.3 Hz), 6.90 (d, 2H, J=7.3 Hz), 6.51(d, 1H, J=15.4 Hz), 6.29 (dt, 1H, J=15.4, 7.7 Hz), 4.22 (t, 2H, J=6.0Hz), 4.06 (s, 2H), 3.06 (t, 2H, J=6.0 Hz), 2.41˜2.46 (m, 4H), 1.89(quint, 2H, 6.9 Hz). MS (ES+) m/e 406 (M+1).

Z-isomer: ¹H NMR (CDCl₃) δ 8.01 (d, 2H, J=7.7 Hz), 7.37 (d, 2H, J=8.5Hz), 7.28 (m, 2H), 6.95 (t, 1H, J=7.7 Hz), 6.90 (d, 2H, J=7.7 Hz), 6.56(d, 1H, J=1.1 Hz), 5.72 (dt, 1H, J=11.1, 6.8 Hz), 4.22 (t, 2H, J=6.0Hz), 4.07 (s, 2H), 3.06 (t, 2H, J=6.0 Hz), 2.51 (m, 2H), 2.37 (t, 2H,J=6.8 Hz), 1.85 (m, 2H). MS (ES+) m/e 406 (M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(6-oxohexen-1-yl)phenyl]-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-cyanopenten-1-yl)phenyl]-1,3,4-oxadiazole(400 mg, 1 mmol) in methylene chloride (10 mL) was cooled to −78° C. and1 M DIBAL-H in hexane (2 mL, 2 mmol) was added dropwise. The mixture wasstirred at −78° C. for 2 h, 1 N HCl (20 mL) was added, and the mixturewas allowed to warmed to room temperature. The mixture was extractedwith methylene chloride (3×10 mL). The combined methylene chlorideextracts were dried (MgSO₄), concentrated, and purified bychromatography (silica gel, ethyl acetate/hexanes 1:4) to give a whitesolid (146 mg, 36%).

E-isomer: ¹H NMR (CDCl₃) δ 9.81 (s, 1H), 7.96 (d, 2H, J=7.7 Hz), 7.45(d, 2H, J=8.6 Hz), 7.28 (m, 2H), 6.96 (t, 1H, J=7.7 Hz), 6.90 (d, 2H,J=7.7 Hz), 6.45 (d, 1H, J=16.3 Hz), 6.33 (dt, 1H, J=16.3, 6.8 Hz), 4.22(t, 2H, J=6.0 Hz), 4.06 (s, 2H), 3.06 (t, 2H, J=6.0 Hz), 2.53 (t, 2H,J=6.0 Hz), 2.31 (dd, 2H, J=10.8, 7.7 Hz), 1.86 (quint, 2H, 7.7 Hz). MS(ES+) m/e 412 (M+1).

Z-isomer: ¹H NMR (CDCl₃) δ 9.78 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.38(d, 2H, J=8.6 Hz), 7.26˜7.29 (m, 2H), 6.95 (t, 1H, J=7.7 Hz), 6.90 (d,2H, J=7.7 Hz), 6.49 (d, 1H, J=11.1 Hz), 5.75 (dt, 1H, J=1 1.1, 6.8 Hz),4.22 (t, 2H, J=6.4 Hz), 4.06 (s, 2H), 3.06 (t, 2H, J=6.0 Hz), 2.48 (t,2H, J=6.8 Hz), 2.39 (m, 2H), 1.81 (m, 2H). MS (ES+) m/e 412 (M+1).

c)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[6-(N,N-dimethylamino)hexen-1-yl]phenyl}-1,3,4-oxadiazole

To a stirred mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(6-oxohexen-1-yl)phenyl]-1,3,4-oxadiazole(103 mg, 0.25 mmol), 2 M dimethylamine in tetrahydrofuran (0.25 mL, 0.5mmol), and acetic acid (15 mg, 0.25 mmol) in 1,2-dichloroethane (2 mL)was added sodium triacetoxyborohydride (106 mg, 0.5 mmol) and stirringwas continued at room temperature for 2 h. 2N NaOH (10 mL) was added andthe mixture was extracted with methylene chloride (3×10 mL). Thecombined methylene chloride extracts were dried (MgSO4), concentrated,and purified by preparative TLC (silica gel, 10% methanol/methylenechloride) to give a white solid (87 mg, 80%).

E-isomer: ¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6Hz), 7.28 (m, 2H), 6.95 (t, 1H, J=7.7 Hz), 6.90 (d, 2H, J=7.7 Hz), 6.43(d, 1H, J=15.4 Hz), 6.36 (dt, 1H, J=15.4, 6.8 Hz), 4.21 (t, 2H, J=6.4Hz), 4.05 (s, 2H), 3.06 (t, 2H, J=6.0 Hz), 2.34 (t, 4H, J=6.8 Hz), 2.29(s, 6H), 2.28 (m, 2H), 1.50˜1.59 (m, 4H). IR (KBr, cm⁻¹) 3070, 3035,2954, 2879, 2684, 1599, 1566, 1475, 1339, 1254, 1057, 921, 748. MS (ES+)m/e 438 (M+1). Anal. Calcd for C₂₅H₃₁N₃O₂S: C, 68.62; H, 7.14; N, 9.60;S, 7.33. Found C, 68.33; H, 7.21; N, 9.47; S, 7.28.

Z-isomer: ¹H NMR (CDCl₃) δ 7.99 (d, 2H, J=7.7 Hz), 7.39 (d, 2H, J=8.6Hz), 7.28 (m, 2H), 6.95 (t, 1H, J=7.7 Hz), 6.90 (d, 2H, J=7.7 Hz), 6.45(d, 1H, J=11.1 Hz), 5.78 (dt, 1H, J=11.1, 7.7 Hz), 4.22 (t, 2H, J=6.4Hz), 4.06 (s, 2H), 3.06 (t, 2H, J=6.4 Hz), 2.37 (m, 2H), 2.29 (m, 2H),2.24 (s, 6H), 1.50˜1.56 (m, 4H). IR (film, cm⁻¹) 3061, 3029, 2943, 2856,2816, 1600, 1508, 1458, 1248, 1061, 913, 743. MS (ES+) m/e 438 (M+1).Anal. Calcd for C₂₅H₃₁N₃O₂S: C, 68.62; H, 7.14; N, 9.60; S, 7.33. FoundC, 68.56; H, 7.20; N, 9.81; S, 7.24.

Example 130 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamino)pentyn-1-yl]phenyl}-1,3,4-oxadiazole

a) 2-{[(2-Phenoxyethyl)thio]methyl}-5-(4-bromophenyl)-1,3,4-oxadiazole

To a mixture of 4-bromobenzoic hydrazide (2.58 g, 12 mmol),2-{[(2-phenoxyethyl)thio]methyl}acetic acid (2.12 g, 10 mmol), and4(N,N-dimethylamino)phenyldiphenylphosphine (9.16 g, 30 mmol) inacetonitrile (100 mL) at 0° C. was added triethylamine (5.06 g, 50 mmol)in carbon tetrachloride (7.69 g, 50 mmol).

After 15 min the cooling bath was removed and the mixture was stirred atroom temperature overnight. The mixture was concentrated toapproximately half the original volume and partitioned between ether(150 mL) and 2 M HCl (100 mL). The ether layer was washed with 2 M HCl(4×30 mL), dried (MgSO₄), and concentrated. The residue was trituratedfrom methylene chloride and hexanes to give white powder (2.80 g, 72%)

¹H NMR (CDCl₃) δ 7.87 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.8 Hz),7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.5 Hz), 6.87 (d, 2H, J=7.7 Hz), 4.19(t, 2H, J=6.2 Hz), 4.04 (s, 2H), 3.03 (t, 2H, J=6.2 Hz). MS (ES+) m/e392 (M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-hydroxypentyn-1-yl)phenyl]-1,3,4-oxadiazole

Palladium (II) acetate (30 mg, 0.13 mmol) and copper (I) iodide (30 mg,0.16 mmol) were added to a solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-bromophenyl)-1,3,4-oxadiazole (782mg, 2 mmol), 4-pentyn-1-ol (186 mg, 2.2 mmol), triphenylphosphine (104mg, 0.4 mmol), and diethylamine (438 mg, 6 mmol) in dimethylsulfoxide(15 mL). The mixture was stirred at 90° C. for 5 h, diluted with water(20 mL), and extracted with ethyl acetate (3×15 mL). The combined ethylacetate extracts were washed with water (2×20 mL) and brine (20 mL),dried (MgSO₄), and concentrated. The residue was purified by columnchromatography (silica gel, ethyl acetate/hexanes 1:2) to give a yellowoil (704 mg, 89%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.5 Hz), 7.47 (d, 2H, J=8.5 Hz),7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz), 4.19(t, 2H, J=6.0 Hz), 4.03 (s, 2H), 3.81 (t, 2H, J=6.2 Hz), 3.03 (t, 2H,J=6.0 Hz), 2.56 (t, 2H, J=6.9 Hz), 1.86 (quint, 2H, J=6.9 Hz). MS (ES+)m/e 395 (M+1).

c)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(methylsulfonyloxy)pentyn-1-yl]phenyl}-1,3,4-oxadiazole

To a solution of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-hydroxypentyn-1-yl)phenyl]-1,3,4-oxadiazole(205 mg, 0.5 mmol) and triethylamine (250 mg, 2.5 mmol) in methylenechloride (5 mL) was added methanesulfonyl chloride (115 mg, 1 mmol). Themixture was stirred at room temperature overnight, diluted with methylenchloride (10 mL), washed with 2 M NaOH (3×10 mL), dried (MgSO₄), andconcentrated to give a yellow oil (235, 100%).

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.4 Hz), 7.48 (d, 2H, J=8.4 Hz),7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz), 4.40(t, 2H, J=6.1 Hz), 4.19 (d, 2H, J=6.0 Hz), 4.04 (s, 2H), 3.03 (t, 2H,J=6.0 Hz), 3.02 (s, 3H), 2.61 (t, 2H, J=6.8 Hz), 2.05 (quint, 2H, J=6.9Hz). MS (ES+) m/e 473 (M+1).

d)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[5-(N,N-dimethylamino)pentyn-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-{4[5-(methylsulfonyloxy)pentyn-1-yl]phenyl}-1,3,4-oxadiazole(220 mg, 0.5 mmol), 2 M dimethylamine in tetrhydrofuran (1 mL, 2 mmol),and potassium carbonate (690 mg, 5 mmol) in acetonitrile (5 mL) wasstirred under reflux overnight. The mixture was cooled to roomtemperature and filtered. The filtrate was concentrated and purified bypreparative TLC (silica gel, 10% methanol/methylene chloride) to give ayellow oil (101 mg, 50%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.4 Hz), 7.47 (d, 2H, J=8.4 Hz),7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.1 Hz), 4.19(d, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.47 (t, 2H,J=7.3 Hz), 2.41 (t, 2H, J=7.3 Hz), 1.81 (s, 6H), 1.77 (quint, 2H, J=7.3Hz). IR (film, cm⁻¹) 3020, 2997, 2946, 2885, 2212, 1406, 1347, 1225,1120, 1088. MS (ES+) m/e 422 (M+1). Anal. Calcd for C₂₄H₂₇N₃O₂S: C,68.38; H, 6.46; N, 9.97; S, 7.61. Found C, 68.26; H, 6.59; N, 9.64; S,7.69.

Example 131 Preparation of(+)-2-{[(2-Phenoxyethyl)thio]methyl]}-5-{4-[3-benzyl-5-(N,N-dimethylamino)pentyn-1-yl]phenyl}-1,3,4-oxadiazole

a) (+)-3-Benzyl-5-hydroxy-1-trimethylsilyl-1-pentyne

A solution of 5-(trimethylsilyl)-4-pentyn-1-ol (20 g, 128 mmol) andN,N,N′,N′-tetramethylethylenediamine (42.5 mL, 282 mmol) in anhydrousTHF (650 mL) was stirred under nitrogen and cooled to −30° C. (dryice/methylene chloride). n-Butyllithium (2.0 M in cyclohexane, 70.5 mL,141 mmol) and t-butyllithium (1.7 M in pentanes, 82.8 mL, 141 mmol) weresequentially added slowly, while the temperature was maintained between−25° and −35° C. After complete addition, the mixture was stirred for 2h, within this temperature range. The mixture was then cooled to −78° C.(dry ice/acetone) and benzyl bromide (16 mL, 134 mmol) intetrahydrofuran (400 mL) was added dropwise while temperature wasmaintained below −60° C. The reaction was then allowed to warm to roomtemperature over 3 h. The reaction was quenched with saturated aqueousammonium chloride (400 mL) and extracted with ethyl ether (2×300 mL).The organic material was dried (Na₂SO₄), filtered and concentrated toyield 35 g of a yellow liquid. This was purified on silica gel (20%ethyl acetate/hexanes) to yield 23.9 g (76%) of a yellow liquid.

¹H NMR (CDCl₃) δ 7.28 (m, 3H), 7.22 (d, 2H, J=7 Hz), 3.79 (dd, 2H, J=5and 6 Hz), 2.74˜2.85 (m, 3H), 2.36 (t, 1H, J=14 Hz), 1.64˜1.77 (m, 2H).MS (ES+) m/e 247 (M+1).

b) (+)-3-Benzyl-5-hydroxy-1-pentyne

A solution (+)-3-benzyl-5-hydroxy-1-trimethylsilyl-1-pentyne (12.5 g,50.8 mmol) in methanol (300 mL) saturated with potassium fluoride wasrefluxed for 1 h. The reaction was cooled to room temperature, dilutedwith brine (100 mL) and extracted with ethyl ether (3×100 mL). Theorganic material was washed with brine (2×50 mL), dried (MgSO₄),filtered and concentrated to yield a colorless liquid. This was purifiedby silica gel (33% ethyl acetate/hexanes) to yield 3.68 g (42%) of acolorless liquid.

¹H NMR (CDCl₃) δ 7.30 (m, 5H), 3.83 (d, 2H, J=4 Hz), 2.77–2.88 (m, 3H),2.12 (s, 1H), 1.78 (m, 1H), 1.66 (m, 1H), 1.53 (br s, 1H). MS (ES+) m/e175 (M+1).

c)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(1-(3-benzyl-5-hydroxypentyn-1-yl)phenyl]-1,3,4-oxadiazole

A mixture containing2-{[(2-phenoxyethyl)thio]methyl}-5-(4-bromophenyl)-1,3,4-oxadiazole (980mg, 2.5 mmol), triphenyl-phosphine (131 mg, 0.5 mmol) and palladium (II)acetate (56 mg, 0.25 mmol) was stirred in anhydrous DMSO (10 mL) at roomtemperature under nitrogen. Solutions of(+)-3-benzyl-5-hydroxy-1-pentyne (480 mg, 2.75 mmol) in methyl sulfoxide(2 mL) and diethylamine (0.78 mL, 7.5 mmol) in methyl sulfoxide (5 mL)were subsequently added, followed by copper (I) iodide (5 mg, 0.025mmol). This mixture was heated to 90° C. for 4 h. The reaction wascooled to room temperature, quenched with water (15 mL) and extractedwith methylene chloride (3×40 mL). The organic material was washed withwater (20 mL), dried (MgSO₄), filtered and concentrated to yield 1.67 gof a brown oil. This oil was purified by silica gel (33% ethylacetate-hexanes) to yield 856 mg (71%) of a colorless oil.

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=9 Hz), 7.44 (d, 2H, J=9 Hz), 7.28 (m,7H), 6.96 (dd, 1H, J=8 and 9 Hz), 6.89 (d, 2H, J=9 Hz), 4.21 (t, 2H,J=12 Hz), 4.06 (s, 2H), 3.89 (d, 2H, J=4 Hz), 3.09 (m, 1H), 3.06 (t, 2H,J=12 Hz), 2.92 (m, 2H), 1.90 (m, 1H), 1.78 (m, 1H), 1.52 (br s, 1H). MS(ES+) m/e 485 (M+1).

d)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-5-(N,N-dimethylamino)pentyn-1-yl]phenyl}-1,3,4-oxadiazole

A solution of(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(1-(3-benzyl-5-hydroxypentyn-1-yl)phenyl]-1,3,4-oxadiazole(250 mg, 0.52 mmol), triethylamine (0.36 mL, 2.58 mmol) andmethanesulfonyl chloride (0.08 mL, 1.04 mmol) were stirred in methylenechloride (5 mL) at room temperature for 16 h. The mixture was dilutedwith methylene chloride (20 mL), extracted with 2N NaOH (20 mL), dried(MgSO₄), filtered and concentrated to yield a quantitative amount of thecorrespoding mesylate. The mesylate was combined with dimethylamine (2.0M in THF, 1.03 mL, 2.06 mmol) and potassium carbonate (720 mg, 5.2 mmol)in actonitrile (10 mL) and refluxed for 6 h. Since the reaction was notcomplete after 6 h., it was allowed to react at room temperature for anadditional 16 h. After filtering the solids, the filtrate wasconcentrated to yield 231 mg of a brown oil. This was purified bypreparative TLC (10% methanol/methylene chloride) to yield 73 mg (27%)of a colorless oil.

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=8 Hz), 7.41 (d, 2H, J=8 Hz), 7.26 (m,7H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=9 Hz), 4.19 (t, 2H,J=12 Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=12 Hz), 2.93 (m, 1H), 2.85 (m,2H), 2.47 (m, 2H), 2.21 (s, 6H), 1.74 (m, 1H), 1.65 (m, 1H). MS (ES+)m/e 512 (M+1). IR (film, cm⁻¹) 3410, 2936, 1601, 1493, 1462, 1239, 752,698. Anal. Calcd for C₃₁H₃₃N₃O₂S: C, 72.77; H, 6.50; N, 8.21; S, 6.27.Found C, 72.45; H, 6.33; N, 8.16; S, 6.18.

Example 132 Preparation of(E)-(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-5-(N,N-dimethylamino)penten-1-yl]phenyl}-1,3,4-oxadiazole

a)(E)-(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(3-benzyl-5-hydroxypenten-1-yl)phenyl]-1,3,4-oxadiazole

A solution containing Red-A1 (65 wt % in toluene, 0.2 mL, 0.67 mmol) inanhydrous tetrahydrofuran (5.5 mL) was stirred in an ice-water bathunder nitrogen. A solution of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(1-(3-benzyl-5-hydroxypentyn-1-yl)phenyl]-1,3,4-oxadiazole(0.27 g, 0.56 mmol) in anhydrous tetrahydrofuran (10 mL) was added andstirring was continued in the cooling bath until the bubbling due tohydrogen evolution had ceased. The bath was then removed and thereaction was refluxed for 2 h. Since the reaction had not completed, themixture was again cooled in an ice-water bath and more Red-A1 (0.1 mL,0.33 mmol) was added. The reaction was refluxed for another 1.5 h untilstarting material was gone. The mixture was then cooled in an ice-waterbath and quenched with water (3 mL). The mixture was then extracted withethyl acetate (2×10 mL). The combined organic material was extractedwith brine (2×110 mL), dried (MgSO₄), filtered and concentrated to yield257 mg of a yellow oil.

This material was purified by chromatography (50% ethyl acetate/hexanes)to yield 34 mg (12%) of a white solid. This procedure was repeated twiceto generate enough material to continue.

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=9 Hz), 7.38 (d, 2H, J=9 Hz), 7.25 (m,4H), 7.16 (m, 3H), 6.93 (dd, 1H, J=7 and 7 Hz), 6.87 (d, 2H, J=8 Hz),6.32 (d, 1H, J=6 Hz), 6.16 (dd, 1H, J=6 and 9 Hz), 4.18 (t, 2H, J=12Hz), 4.03 (s, 2H), 3.68 (m, 2H), 3.03 (t, 2H, J=12 Hz), 2.75 (d, 2H, J=7Hz), 2.52 (m, 1H), 1.81 (m, 1H), 1.63 (m, 1H), 1.20 (m, 1H). MS (ES+)m/e 487 (M+1).

b)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-5-(methylsulfonyloxy)penten-1-yl]phenyl}-1,3,4-oxadiazole

To a solution of(E)-(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(3-benzyl-5-hydroxypenten-1-yl)phenyl]-1,3,4-oxadiazole(60 mg, 0.12 mmol) and triethylamine (50 mg, 0.5 mmol) in methylenechloride (2 mL) at 0° C. was added methanesulfonyl chloride (29 mg, 0.25mmol). The resultant mixture was stirred at room temperature overnight,diluted with methylene chloride (20 mL), washed with 2 M HCl (5 mL) and2 M NaOH (5 mL), dried (MgSO₄), and concentrated to give a yellow oil(61 mg, 90%).

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.6 Hz), 7.38 (d, 2H, J=8.6 Hz),7.20˜7.31 (m, 4H), 7.18 (t, 1H, J=7.0 Hz), 7.14 (d, 2H, J=7.0 Hz), 6.93(t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.35 (d, 1H, J=15.6 Hz), 6.10(dd, 1H, J=15.6, 8.9 Hz), 4.20˜4.26 (m, 2H), 4.19 (d, 2H, J=6.2 Hz),4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.91 (s, 3H), 2.76 (d, 2H, J=6.3Hz), 2.03 (m, 1H), 1.75 (m, 1H), 1.38 (m, 1H). MS (ES+) m/e 565 (M+1).

c)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-5-(N,N-dimethylamino)penten-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-5-(methylsulfonyloxy)penten-1-yl]phenyl}-1,3,4-oxadiazole(61 mg, 0.11 mmol), 2 M dimethylamine in tetrahydrofuran (0.6 mL, 1.2mmol), and potassium carbonate (166 mg, 1.2 mmol) in acetonitrile (10mL) was stirred under reflux for 20 h and filtered. The filtrate wasconcentrated and purified by preparative TLC (silica gel, 10%methanol/methylene chloride) to give a white solid (32 mg, 57%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.6 Hz), 7.38 (d, 2H, J=8.6 Hz),7.13˜7.26 (m, 7H), 6.93 (t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.28(d, 1H, J=16.4 Hz), 6.13 (dd, 1H, J=16.3, 8.5 Hz), 4.18 (t, 2H, J=6.2Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.74 (d, 2H, J=7.0 Hz), 2.55(m, 1H), 2.32 (t, 2H, J=7.8 Hz), 2.21 (s, 6H), 1.74 (m, 1H), 1.55 (m,1H). IR (KBr, cm⁻¹) 3032, 2955, 2906, 1600, 1557, 1476, 1348, 1179,1126, 747. MS (ES+) m/e 514 (M+1). Anal. Calcd for C₃₁H₃₅N₃O₂S: C,72.48; H, 6.87; N, 8.18; S, 6.24. Found C, 71.91; H, 6.81; N, 8.23; S,6.34.

Example 133 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[4-(N,N-dimethylamino)buten-1-yl]phenyl}-1,3,4-oxadiazole

a)2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(4-hydroxybutyn-1-yl)phenyl]-1,3,4-oxadiazole

A mixture containing2-{[(2-phenoxyethyl)thio]methyl}-5-(4-bromophenyl)-1,3,4-oxadiazole (5g, 12.8 mmol), triphenyl-phosphine (0.67 g, 2.56 mmol) and palladium(II) acetate (287 mg, 1.28 mmol) was stirred in anhydrousdimethylsulfoxide (50 mL) at room temperature under nitrogen. Solutionsof 3-butyn-1-ol (1.07 mL, 14.1 mmol) in dimethylsulfoxide (10 mL) anddiethylamine (4 mL, 38.4 mmol) in dimethylsulfoxide (10 mL) weresubsequently added, followed by copper (I) iodide (25 mg, 0.128 mmol).This mixture was heated to 90° C. for 3 h. The reaction was cooled toroom temperature, quenched with water (75 mL) and extracted with ethylacetate (3×100 mL). The organic material was washed with brine (3×50mL), dried (MgSO₄), filtered and concentrated to yield 5.92 g of a brownoil. This oil was purified by silica gel (50% ethyl acetate/hexanes) toyield 1.91 g (39%) of a colorless oil.

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8 Hz), 7.50 (d, 2H, J=8 Hz), 7.28 (m,2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz), 4.19 (t, 2H,J=12 Hz), 4.03 (s, 2H), 3.83 (dd, 2H, J=6 and 12 Hz), 3.09 (m, 1H), 3.04(t, 2H, J=12 Hz), 2.71 (t, 2H, J=12 Hz), 1.76 (t, 1H, J=12 Hz). MS (ES+)m/e 381 (M+1).

b)(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(4-hydroxybuten-1-yl)phenyl]-1,3,4-oxadiazole

A solution containing Red-A1 (0.73 mL, 2.4 mmol) in anhydroustetrahydrofuran (12 mL) was stirred in an ice-water bath under nitrogen.A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(4-hydroxybutyn-1-yl)phenyl]-1,3,4-oxadiazole(0.76 g, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added andstirring was continued in the cooling bath until the bubbling due tohydrogen evolution had ceased. The bath was then removed and thereaction was refluxed for 1 h. Even though some of the alkyne startingmaterial was present, the reaction was stopped here because TLCindicated that the product was decomposing. The mixture was then cooledin an ice-water bath and quenched with water (5 mL). The mixture wasdiluted with more water (10 mL) and then extracted with ethyl acetate(3×30 mL). The combined organic material was extracted with brine (2×20mL), dried (MgSO₄), filtered and concentrated to yield 890 mg of ayellow oil which contained products and the alkyne starting material.This material was purified by preparative TLC (50% ethylacetate/hexanes) to yield 128 mg (22%, based on converted startingmaterial) of a white solid and 187 mg of alkyne starting material.

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8 Hz), 7.45 (d, 2H, J=8 Hz), 7.25 (m,4H), 7.25 (m, 2H), 6.94 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz),6.52 (d, 1H, J=15 Hz), 6.36 (m, 1H), 4.18 (t, 2H, J=12 Hz), 4.03 (s, 21,3.78 (m, 2H), 3.03 (t, 2H, J=12 Hz), 2.75 (d, 2H, J=7 Hz), 2.52 (m, 2H),1.43 (m, 1H). MS (ES+) m/e 383 (M+1).

c)(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[4-(methylsulfonyloxy)buten-1-yl]phenyl}-1,3,4-oxadiazole

To a solution of(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(4-hydroxybuten-1-yl)phenyl]-1,3,4-oxadiazole(120 mg, 0.31 mmol) and triethylamine (121 mg, 1.2 mmol) in methylenchloride (3 mL) at 0° C. was added methanesulfonyl chloride (69 mg, 0.6mmol). The resultant mixture was stirred at room temperature overnight,diluted with methylene chloride (20 mL), washed with 2 M HCl (5 mL) and2 M NaOH (5 mL), dried (MgSO₄), and concentrated to give yellow oil (138mg, 97%).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6 Hz),7.22˜7.27 (m, 2H), 6.93 (t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.54(d, 1H, J=16.4 Hz), 6.28 (dt, 1H, J=16.4, 7.0 Hz), 4.34 (t, 2H, J=6.2Hz), 4.19 (t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=6.2 Hz), 3.01(s, 3H), 2.68 (m, 2H). MS (ES+) m/e 461 (M+1).

d)(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{1[4-(N,N-dimethylamino)buten-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[4-(methylsulfonyloxy)buten-1-yl]phenyl}-1,3,4-oxadiazole(120 mg, 0.29 mmol), 2 M dimethylamine in tetrahydrofuran (1.5 mL, 3mmol), and potassium carbonate (400 mg, 2.9 mmol) in acetonitrile (15mL) was stirred under reflux for 20 h and filtered. The filtrate wasconcentrated and purified by preparative TLC (silica gel, 10%methanol/methylene chloride) to give a white solid (111 mg, 93%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=7.8 Hz), 7.43 (d, 2H, J=8.6 Hz),7.22˜7.27 (m, 2H), 6.93 (t, 1H, J=7.4 Hz), 6.87 (d, 2H, J=7.6 Hz), 6.46(d, 1H, J=15.6 Hz), 6.35 (dt, 1H, J=15.6, 6.2 Hz), 4.19 (t, 2H, J=6.2Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.2 Hz), 2.40˜2.49 (m, 4H), 2.28 (s,6H). IR (KBr, cm⁻¹) 3032, 2960, 2931, 2880, 1589, 1553, 1499, 1239,1094, 1042, 746. MS (ES+) m/e 410 (M+1). Anal. Calcd for C₂₃H₂₇N₃O₂S: C,67.45; H, 6.65; N, 10.26; S, 7.83. Found C, 67.32; H, 6.68; N, 10.50; S,7.88.

Example 134 Preparation of(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-aminopropen-1-yl)phenyl]-1,3,4-oxadiazole

a) 1-tert-Butoxycarbonylaziridine

A solution containing ethanolamine (6 g, 98.2 mmol) and di-tert-butyldicarbonate (23.6 g, 108 mmol) in isopropyl alcohol (40 mL) and dioxane(80 mL) was stirred at room temperature for 3 hr. The mixture wasconcentrated and dried under vacuum overnight. This material was thencombined with p-toluenesulfonyl chloride (22.5 g, 117.8 mmol) andpowdered KOH (22.0 g, 392.8 mmol) in ethyl ether (800 mL). The mixturewas refluxed for 1.5 days, but only 50% was converted. More KOH (11 g,146 mmol) was added, the heat was removed and the reaction stirred 2days at room temperature. The mixture was poured over ice-water (600 mL)and the organic material was separated. The aqueous layer was extractedwith ethyl ether (200 mL) and the combined organic extracts were dried(MgSO₄), filtered and concentrated at 1 atm to remove most of the ether.The flask was left open in the hood overnight to allow completeevaporation of ether to yield 14 g (99%) of a colorless oil.

¹H NMR (CDCl₃) δ 2.11 (s, 4H), 1.43 (s, 9H).

b) Methyl 4-{3-[(tert-butoxycarbonyl)amino]propen-1-yl}benzoate

A solution containing methyl 4-formylbenzoate (2.7 g, 16.45 mmol),1-(tert-butoxycarbonyl)aziridine (7.07 g, 49.4 mmol), andtriphenylphosphine (12.9 g, 49.4 mmol) in isopropyl alcohol (150 mL) wasrefluxed for 3 h. The reaction was concentrated to yield 4.63 g of acolorless oil which contained an approximately 1:3 ratio of Z-olefin(top spot on TLC) to E-olefin (bottom spot). This material was purifiedon silica gel (20% ethyl acetate/hexanes) to yield 1.24 g (26%) of awhite solid (E-isomer). Another 2.2 g (46%) of E/Z mixture was isolated,too.

E-isomer: ¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.38 (d, 2H, J=8 Hz),6.51 (d, 1H, J=16 Hz), 6.29 (m, 1), 4.68 (br s, 1H), 3.91 (m, 2H), 3.88(s, 3H), 1.44 (s, 9H). MS (ES+) m/e 292 (M+1).

c) 4-{3-[(tert-butoxycarbonyl)amino]propen-1-yl}benzoic acid, (E)- and(Z)-isomers

To a solution of methyl4-{3-[(tert-butoxycarbonyl)amino]propen-1-yl}benzoate (1.46 g, 5 mmol)in 1,4-dioxane (25 mL) was added 2 M NaOH (25 mL, 50 mmol) and thereaction was stirred at room temperature for 3 h. Ice (30 g) was addedand the mixture was acidified with 2 M HCl (26 mL) and extracted withmethylene chloride (3×30 mL). The combined methylene chloride extractswere washed with water (2×50 mL), dried (MgSO₄), and concentrated togive a white solid (1.20 g, 86%).

E-isomer: ¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.6 Hz), 7.52 (d, 2H, J=8.8Hz), 6.59 (d, 1H, J=15.6 Hz), 6.43 (dt, 1H, J=15.6, 5.5 Hz), 6.19 (br s,1H), 3.87 (m, 2H), 1.41 (s, 9H). MS (ES−) m/e 276 (M−1).

Z-isomer: ¹H NMR (CDCl₃) δ 8.04 (d, 2H, J=7.8 Hz), 7.29 (d, 2H, J=8.6Hz), 6.55 (d, 1H, J=11.7 Hz), 5.77 (dt, 1H, J=11.7, 6.0 Hz), 4.64 (br s,1H), 4.03 (m, 2H), 1.43 (s, 9H). MS (ES−) m/e 276 (M−1).

d)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-((tert-butoxycarbonyl)amino)propen-1-yl]phenyl}-1,3,4-oxadiazole,(E)- and (Z)-isomers

To a stirred mixture of4-{3-[(tert-butoxycarbonyl)amino]propen-1-yl}benzoic acid (1.11 g, 4mmol), 2-(2-phenoxyethyl)thioacetic hydrazide hydrochloride (1.16 g, 4.4mmol), and p-(N,N-dimethylamino)phenyldiphenylphosphine (3.66 g, 12mmol) in acetonitrile (40 mL) at 0° C. was added a solution oftriethylamine (2.43 g, 24 mmol) in carbon tetrachloride (3.08 g, 20mmol). After 10 min the cooling bath was removed and stirring wascontinued at room temperature overnight. The mixture was concentrated toapproximately half the original volume and partitioned between ether(100 mL) and 2 M HCl (100 mL). The ether layer was washed with 2 M HCl(4×50 mL) and water (50 mL), dired (MgSO₄) and concentrated. The residuewas purified by column chromatography (silica gel, ethyl acetate/hexanes1:2) to give a colorless oil (1.23 g, 66%).

E-isomer: ¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=7.9Hz), 7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz),6.52 (d, 1H, J=16.4 Hz), 6.31 (dt, 1H, J=16.6, 6.3 Hz), 4.67 (br s, 1H),4.19 (t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.93 (m, 2H), 3.03 (t, 2H, J=6.2Hz), 1.45 (s, 9H). MS (ES+) m/e 468 (M+1).

Z-isomer: ¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=8.6 Hz), 7.32 (d, 2H, J=8.5Hz), 7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=7.8 Hz),6.54 (d, 1H, J=11.7 Hz), 5.76 (dt, 1H, J=11.7, 6.3 Hz), 4.62 (br s, 1H),4.18 (t, 2H, J=6.2 Hz), 4.06 (m, 2H), 4.04 (s, 2H), 3.04 (t, 2H, J=6.2Hz), 1.43 (s, 9H). MS (ES+) m/e 468 (M+1).

e)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-aminopropen-1-yl)phenyl]-1,3,4-oxadiazole,(E)- and (Z)-isomers

Trifluoroacetic acid (2 mL) was added slowly to a solution of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[3-((tert-butoxycarbonyl)amino)propen-1-yl]phenyl}-1,3,4-oxadiazole(467 mg, 1 mmol) in methylene chloride (8 mL). The mixture was stirredat room temperature for 1 h and concentrated. The residue waspartitioned between 2 M NaOH (10 mL) and methylene chloride (20 mL), andthe aqueous layer was extracted with methylene chloride (15 mL). Thecombined methylene chloride extracts were dried (MgSO₄) andconcentrated. The residue was triturated from methylene and hexanes togive a white powder (323 mg, 88%).

E-isomer: ¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.6 Hz), 7.46 (d, 2H, J=8.6Hz), 7.23˜7.26 (m, 2H), 6.93 (t, 1H, J=7.1 Hz), 6.87 (d, 2H, J=7.8 Hz),6.54 (d, 1H, J=16.3 Hz), 6.44 (dt, 1H, J=15.6, 5.5 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.03 (s, 2H), 3.51 (d, 2H, J=5.5 Hz), 3.04 (t, 2H, J=6.2 Hz).IR (KBr, cm⁻¹) 3430, 3029, 2952, 2945, 2858, 1600, 1563, 1504, 1461,1244, 1175, 752. MS (ES+) m/e 368 (M+1). Anal. Calcd for C₂₀H₂₁N₃O₂S: C,65.37; H, 5.76; N, 11.43; S, 8.73. Found C, 65.58; H, 6.01; N, 11.20; S,8.61.

Z-isomer: ¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8.6 Hz), 7.32 (d, 2H, J=8.7Hz), 7.22˜7.27 (m, 2H), 6.93 (t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz),6.47 (d, 1H, J=11.7 Hz), 5.84 (dt, 1H, J=11.7, 5.8 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.04 (s, 2H), 3.60 (d, 2H, J=6.2 Hz), 3.04 (t, 2H, J=6.3 Hz).IR (KBr, cm⁻¹) 3430, 3031, 2950, 2945, 2841, 1599, 1550, 1486, 1410,1235, 1147, 755. MS (ES+) m/e 368 (M+1). Anal. Calcd for C₂₀H₂₁N₃O₂S: C,65.37; H, 5.76; N, 11.43; S, 8.73. Found C, 64.97; H, 5.94; N, 11.26; S,8.83.

Example 135 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-(N,N-dimethylamino)propen-1-yl]phenyl}-1,3,4-oxadiazole,(E)- and (Z)-isomers

A mixture of2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-aminopropen-1-yl)phenyl]-1,3,4-oxadiazole(229 mg, 0.62 mmol) and parafomaldehyde (187 mg, 6.2 mmol) in methanol(6 mL) was stirred under reflux for 3 h and then cooled to roomtemperature. Sodium cyanoborohydride (117 mg, 1.86 mmol) was added inthree portions and the resultant mixture was stirred at room temperaturefor 2 h. The reaction was quenched by addition of water (0.5 mL) andmost of the methanol was evaporated. The residue was diluted withsaturated sodium bicarbonate (10 mL) and extracted with methylenechloride (3×10 mL). The combined methylene chloride extracts were dried(MgSO₄) and concentrated. The residue was purified by preparative TLC(silica gel, 10% methanol/methylene chloride) to give a pale yellowsolid (176 mg, 72%).

E-isomer: ¹H NMR (CDCl₃) δ7.95 (d, 2H, J=8.6 Hz), 7.46 (d, 2H, J=8.6Hz), 7.22˜7.27 (m, 2H), 6.93 (t, 1H, J=7.8 Hz), 6.87 (d, 2H, J=7.8 Hz),6.54 (d, 1H, J=15.6 Hz), 6.38 (dt, 1H, J=16.4, 6.3 Hz), 4.19 (t, 2H,J=6.2 Hz), 4.03 (s, 2H), 3.11 (d, 2H, J=6.3 Hz), 3.04 (t, 2H, J=6.2 Hz),2.28 (s, 6H). IR (film, cm⁻¹) 3030, 2952, 2928, 2884, 1598, 1552, 1481,1293, 1065, 739. MS (ES+) m/e 396 (M+1). Anal. Calcd for C₂₂H₂₅N₃O₂S: C,66.81; H, 6.37; N, 10.62; S, 8.11. Found C, 67.05; H, 6.28; N, 10.79; S,8.04.

Z-isomer: ¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=7.8 Hz), 7.35 (d, 2H, J=7.8Hz), 7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.4 Hz), 6.87 (d, 2H, J=7.8 Hz),6.58 (d, 1H, J=11.7 Hz), 5.90 (dt, 1H, J=12.5, 6.2 Hz), 4.18 (t, 2H,J=6.2 Hz), 4.04 (s, 2H), 3.20 (d, 2H, J=6.2 Hz), 3.04 (t, 2H, J=6.2 Hz),2.25 (s, 6H). IR (film, cm⁻¹) 3031, 2980, 2963, 1600, 1552, 1481, 1295,1055, 983, 750. MS (ES+) m/e 396 (M+1). Anal. Calcd for C₂₂H₂₅N₃O₂S: C,66.81; H, 6.37; N, 10.62; S, 8.11. Found C, 67.37; H, 6.50; N, 10.43; S,8.03.

Example 136 Preparation of(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(3-pyrrolidinopropen-1-yl)phenyl]-1,3,4-oxadiazole

A suspension containing(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(3-aminopropen-1-yl)phenyl]-1,3,4-oxadiazole(135 mg, 0.367 mmol) and 1,4-butanedial bisulfite adduct (121 mg, 0.367mmol) was stirred in methanol (4 mL). Sodium cyanoborohydride (46.1 mg,0.734 mmol) was added and the reaction stirred for 72 h. The reactionwas quenched with 2N aqueous NaOH (2 mL), extracted with methylenechloride (3×5 mL), dried (MgSO₄) and filtered to yield 147 mg of ayellow oil. This material was purified by preparative TLC (10%methanol/methylene chloride) to yield 55 mg (36%) of a yellow solid.

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 7.24 (m,2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz), 6.57 (d, 1H,J=16 Hz), 6.45 (dd, 1H, J=7 and 16 Hz), 4.18 (t, 2H, J=12 Hz), 4.03 (s,2H), 3.31 (d, 2H, J=6 Hz), 3.03 (t, 2H, J=12 Hz), 2.60 (m, 4H), 1.81 (m,4H). IR (film, cm⁻¹) 3428, 2952, 2930, 2787, 1596, 1493, 1241, 755. MS(ES+) m/e 422 (M+1). Anal. Calcd for C₂₄H₂₇N₃O₂S: C, 68.38; H, 6.46; N,9.97; S, 7.61. Found C, 68.52; H, 6.38; N, 9.89; S, 7.70.

Example 137 Preparation of2-{[(2-phenoxyethyl)amino]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

a) 2-(2-Nitrobenzensulfonamido)ethyl phenyl ether

To a stirred mixture of 2-phenoxyethylamine (3.29 g, 24 mmol) andpotassium bicarbonate (10 g, 100 mmol) in methylene chloride (200 mL)was added 2-nitrobenzenesulfonyl chloride (4.43 g, 20 mmol) in severalportions. The resultant mixture was stirred at room temperatureovernight and filtered. The filtrate was washed with 2 M HCl (3×30 mL),dried (MgSO₄), and concentrated. The residue was triturated frommethylene chloride/hexanes to give a white solid (5.7 g, 88%).

¹H NMR (CDCl₃) δ 8.13 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz),7.63˜7.71 (m, 2H), 7.18˜7.24 (m, 2H), 6.92 (t, 1H, J=7.3 Hz), 6.71 (d,2H, J=8.0 Hz), 5.90 (br t, 1H, J=5.5 Hz), 4.0 (t, 2H, J=5.1 Hz), 3.52(t, 2H, 5.5 Hz). MS (ES+) m/e 323 (M+1).

b)N-[(Methoxycarbonyl)methyl]-N-(2-phenoxyethyl)-2-nitrobenzenesulfonamide

To a stirred mixture of 2-(2-nitrobenzensulfonamido)ethyl phenyl ether(1.61 g, 5 mmol) and potassoum carbonate (6.91 g, 50 mmol) intetrahydrofuran (50 mL) was added sodium iodide (300 mg, 2 mmol) andmethyl bromoacetate (1.53 g, 10 mmol) and stirring was continued at roomtemperature overnight. The mixture was diluted with ethyl acetate (25mL), washed with water (2×30 mL) and brine (25 mL), dried (MgSO₄), andconcentrated to give yellow oil (1.99 g, 100%).

¹H NMR (CDCl₃) δ 8.08 (d, 1H, J=8.8 Hz), 7.60˜7.68 (m, 3H), 7.24 (m,2H), 6.93 (t, 1H, J=7.3 Hz), 6.77 (d, 2H, J=8.8 Hz), 4.37 (s, 2H), 4.15(t, 2H, J=4.8 Hz), 3.80 (t, 2H, J=4.8 Hz), 3.56 (s, 3H). MS (ES+) m/e395 (M+1).

c) 2-[N-(2-phenoxyethyl)-2-nitrobenzenesulonamido]acetic hydrazide

A mixture of methylN-[(methoxycarbonyl)methyl]-N-(2-phenoxyethyl)-2-nitrobenzenesulfonamide(1.97 g, 5 mmol) and hydrazine monohydrate (2.5 g, 50 mmol) in ethanolwas stirred at room temperature overnight and concentrated. Excesshydrazine was also removed under vacuum. The residue was taken up inethyl acetate (75 mL) and washed with water (2×50 mL), dried (MgSO₄),and concentrated to give a yellow oil (1.73 g, 88%).

¹H NMR (CDCl₃) δ 8.06 (d, 1H, J=7.7 Hz), 7.65˜7.74 (m, 3H), 7.23˜7.27(m, 2H), 6.95 (t, 1H, J=7.3 Hz), 6.80 (d, 2H, J=8.4 Hz), 4.15 (t, 2H,J=5.0 Hz), 4.12 (s, 2H), 3.81 (t, 2H, J=5.0 Hz), 3.56 (s, 3H). MS (ES+)m/e 395 (M+1).

d)2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-{4-[(tert-butoxycarbonyl)amino]phenyl}-1,3,4-oxadiazole

To a stirred mixture of2-[N-(2-phenoxyethyl)-2-nitrobenzenesulonamido]acetic hydrazide (1.58 g,4 mmol), 4-(tert-butyloxycarbonyl)bezoic acid (1.19 g, 5 mmol), and4-(N,N-dimethylamino)phenyldiphenylphosphine (4.58 g, 15 mmol) inacetonitrile (50 mmol), at 0° C., was added a solution of triethylamine(2.56 g, 25 mmol) in carbon tetrachloride (3.85 g, 25 mmol). After 10min the cooling bath was removed and stirring was continued at roomtemperature overnight. The resultant mixture was concentrated toapproximately half the original volume and partitioned between ether(150 mL) and 2 M HCl (100 mL). The organic layer was washed with 2 M HCl(3×150 mL) and 2 M NaOH (3×50 mL), dried (MgSO₄), and concentrated togive a brown oil (1.81 g, 76%).

¹H NMR (CDCl₃) δ 8.04 (d, 1H, J=8.8 Hz), 7.77 (d, 2H, J=8.8 Hz),7.43˜7.67 (m, 5H), 7.19 (t, 2H, J=8.0 Hz), 6.90 (t, 1H, J=7.3 Hz), 6.71(d, 2H, J=7.7 Hz), 5.04 (s, 2H), 4.19 (t, 2H, J=5.1 Hz), 3.90 (t, 2H,J=5.1 Hz), 1.51 (s, 9H). MS (ES+) m/e 596 (M+1).

e)2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole

Trifluoroacetic acid (2.5 mL) was added to a solution of2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-{4-[(tert-butoxycarbonyl)amino]phenyl}-1,3,4-oxadiazole(1.19 g, 2 mmol) in methylene chloride (7.5 Ml). The mixture was stirredat room temperature for 3 h and concentrated. The residue was dissolvedin methylene chloride (15 mL) and washed with 2 M NaOH (15 mL), dired(MgSO₄), and concentrated. The residue was purified by columnchromatography (silica gel, ethyl acetate/hexanes) to give a pale yellowoil (400 mg, 40%).

¹H NMR (CDCl₃), δ 8.09 (d, 1H, J=7.4 Hz), 7.57˜7.66 (m, 5H), 7.22 (m,2H), 6.90 (t, 1H, J=7.3 Hz), 6.71 (d, 2H, J=8.0 Hz), 6.65 (d, 2H, J=8.8Hz), 5.01 (s, 2H), 4.18 (t, 2H, J=5.0 Hz), 3.90 (t, 2H, J=5.0 Hz). MS(ES+) m/e 496 (M+1).

f)2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

To a stirred mixture of2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole(248 mg, 0.5 mmol), 4-(N,N-dimethylamino)butanoic acid hydrochloride(168 mg, 1 mmol), and 1-hydroxybenzotriazole (135 mg, 1 mmol) inN,N-dimethylformamide (5 mL) was added diisopropylcarbodiimide (126 mg,1 mmol) and stirring was continued at room temperature overnight. Themixture was diluted with ethyl acetate (25 mL), washed with 2 M NaOH(3×10 mL), water (2×10 mL), and brine (10 mL), dried (MgSO₄), andconcentrated. The residue was purified by chromatography (silica gel,20% methanol/methylene chloride) to give a pale yellow oil (228 mg,75%).

¹H NMR (CDCl₃) δ 10.68 (s, 1H), 8.10 (d, 1H, J=9.1 Hz), 7.77 (d, 2H,J=8.8 Hz), 7.58˜7.65 (m, 5H), 7.19 (m, 2H), 6.90 (t, 1H, J=7.3 Hz), 6.71(d, 2H, J=7.7 Hz), 5.04 (s, 2H), 4.19 (t, 2H, J=4.9 Hz), 3.90 (t, 2H,J=4.9 Hz), 2.49˜2.56 (m, 4H), 2.36 (s, 6H), 1.86 (m, 2H). MS (ES+) m/e609 (M+1).

g)2-{[(2-phenoxyethyl)amino]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

A mixture of2-{[N-(2-nitrobenzenesulfonyl)-(2-phenoxyethyl)amino]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(152 mg, 0.25 mmol) and potassium carbonate (104 mg, 0.75 mmol) inN,N-dimethylformamide (1.5 mL) was stirred at room temperature andbenzenethiol (33 mg, 0.3 mmol) was added. Stirring was continued for 3 hand the mixture was diluted with water (5 mL) and extracted with ethylacetate (8 mL). The ethyl acetate extract was loaded to a cationexchange column (Bio-Rad 50W-x2 resin) and eluted with methanol. Thebasic material was recovered by flushing the column with 2 M ammonia inmethanol and further purified by preparative TLC (silica gel, 10%methanol/methylene chloride) to give a pale yellow oil (71 mg, 67%).

¹H NMR (CDCl₃) δ 10.59 (s, 11, 7.95 (d, 1H, J=8.8 Hz), 7.65 (d, 2H,J=8.8 Hz), 7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.1Hz), 4.16 (s, 2H), 4.08 (t, 2H, J=5.0 Hz), 3.11 (t, 2H, J=5.0 Hz),2.49˜2.56 (m, 41), 2.36 (s, 6H), 1.88 (m, 21). IR (film, cm⁻¹) 3483,3340, 2948, 2925, 1661, 1605, 1500, 1428, 1182, 1067, 1027, 756. MS(ES+) m/e 424 (M+1). Anal. Calcd for C₂₃H₂₉N₅O₃: C, 65.23; H, 6.90; N,16.54. Found C, 65.01; H, 6.96; N, 16.77.

Example 137 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N′,N′-dimethyl-1,3-propanediamino)methyl]phenyl}-1,3,4-oxadiazole

a) 2-[4-(hydroxycarbonyl)phenyl]-1,3-dioxolane

Aluminum oxide (Brockmann I, basic, 150 mesh, 34 g, 0.33 mol) was addedto a solution of 4-carboxybenzaldehyde (20 g, 0.13 mol) and ethyleneglycol (83 g, 1.3 mol) in toluene (700 mL). The resulting suspension wasrefluxed for 24 h. After cooling, the solids were filtered and washedwith ethyl acetate (300 mL). The filtrate was extracted with water(10×100 mL), dried (MgSO₄), filtered and concentrated to yield 15.9 g(61%) of a white solid that required no further purification.

¹H NMR (CDCl₃) δ 8.09 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 5.86 (s,H), 4.07 (m, 4H). MS (ES−) m/e 193 (M−1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole

A suspension containing 2-[4-(hydroxycarbonyl)phenyl]-1,3-dioxolane(6.55 g, 33.7 mmol), 2-[(2-phenoxyethyl)thio]acetic acid hydrazide,hydrochloride salt (10.63 g. 40.4 mmol) and4-(dimethylamino)phenyldiphenylphosphine (30.9 g, 101.1 mmol) was cooledin an ice/water bath. Triethylamine (28.2 mL, 202.3 mmol) and carbontetrachloride (16.3 mL, 168.6 mmol) were combined and added dropwiseover 5 min. The reaction stirred in the bath for 10 min, then stirred atroom temperature for 16 h. The solution was concentrated to about 10% ofits original volume and diluted with ethyl ether (300 mL) and 2 NHCl(200 mL). The organic phase was further extracted with 2 N HCl (6×100mL), dried (MgSO₄), filtered and concentrated to yield 8 g (62%) of ayellow solid that was not further purified.

¹H NMR (CDCl₃) δ 8.03 (d, 2H, J=7 Hz), 7.59 (d, 2H, J=7 Hz), 7.24 (m,2H), 6.88 (m, 3H), 5.85 (s, 1H), 4.20 (m, 2H), 4.12 (m, 2H), 4.07 (m,2H), 4.04 (m, 2H), 3.04 (m, 211). MS (ES+) m/e 385 (M+1).

c) 2-{[(2-Phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole

A solution2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole(8.0 g, 20.8 mmol) and pyridinium p-toluenesulfonate (1.0 g, 4.0 mmol)and water (5 mL) in acetone (200 mL) was refluxed for 6 h, cooled andconcentrated. The residue was diluted with ethyl acetate (250 mL) andwashed with saturated aqueous sodium bicarbonate (3×60 mL), dried(MgSO₄), filtered and concentrated. This residue was purified oversilica gel (25% ethyl acetate/hexanes) to yield 2.22 g (31%) of a whitesolid.

¹H NMR (CDCl₃) δ 10.08 (s, 1H), 8.18 (d, 2H, J=7 Hz), 7.99 (d, 2H, J=7Hz), 7.26 (m, 21), 6.93 (m, 1H), 6.87 (d, 2H, J=8 Hz), 4.20 (t, 2H, J=11Hz), 4.07 (s, 2H), 3.05 (t, 2H, J=11 Hz). MS (ES+) m/e 341 (M+1).

d)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[(N′,N′-dimethyl-1,3-propanediamino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(200 mg, 0.59 mmol), 3-(N,N-dimethylamino)propylamine (0.08 mL, 0.64mmol) and glacial acetic acid (0.03 mL, 0.59 mmol) in 1,2-dichloroethane(3.0 mL) was stirred under nitrogen at room temperature. Sodiumtriacetoxyborohydride (190 mg, 0.88 mmol) was added and the reactionstirred for 5 h. The mixture was then diluted with methylene chloride (5mL), washed with 2 N NaOH (10 mL), dried (MgSO₄), filtered andconcentrated to yield 0.29 g of a pale yellow oil. This material waspurified by preparative TLC [90% methylene chloride/5% methanol/5% (2.0M ammonia/methanol)] to yield 164 mg (66%) of a colorless oil.

¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8 Hz), 7.44 (d, 2H, J=8 Hz), 7.25 (m,2H), 6.93 (m, 1H), 6.87 (d, 2H, J=8 Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s,2H), 3.84 (s, 2H), 3.04 (t, 2H, J=12 Hz), 2.68 (t, 2H, J=14 Hz), 2.34(t, 2H, J=14 Hz), 2.22 (s, 6H), 1.72 (m, 2H). MS (ES+) m/e 427 (M+1). IR(film, cm⁻¹) 3458, 3425, 3397, 1640, 1591, 1491, 1241. Anal. Calcd forC₂₃H₃₀N₄O₂S: C, 64.76; H, 7.09; N, 13.13; S, 7.52. Found C, 64.40; H,6.98; N, 13.29; S, 7.80.

Example 138 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{[4-[(N,N′,N′-trimethyl-1,2-ethanediamino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(200 mg, 0.59 mmol), N,N,N′-trimethylethylenediamine (0.15 mL, 1.18mmol) and glacial acetic acid (0.03 mL, 0.59 mmol) in 1,2-dichloroethane(3.0 mL) was stirred under nitrogen at room temperature. Sodiumtriacetoxyborohydride (190 mg, 0.88 mmol) was added and the reactionstirred for 3 h. The mixture was then diluted with methylene chloride (5mL), washed with 2 N NaOH (10 mL), dried (MgSO₄), filtered andconcentrated to yield 0.31 g of a pale yellow oil. This material waspurified by preparative TLC [90% methylene chloride/5% methanol/5% (2.0M ammonia/methanol)] to yield 172 mg (69%) of a white solid.

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=6 Hz), 7.44 (d, 2H, J=6 Hz), 7.25 (m,2H), 6.93 (1,1H), 6.87 (d, 2H, J=7 Hz), 4.19 (m, 2H), 4.03 (s, 2H), 3.56(s, 2H), 3.04 (m, 2H), 2.48 (m, 4H), 2.24 (s, 3H), 2.22 (s, 6H). IR(KBr, cm⁻¹) 3419, 2945, 2802, 2763, 1594, 1559, 1493, 1460, 1416, 1310,1237, 1180, 1136, 1083, 1029, 851, 752, 693. MS (ES+) m/e 427 (M+1).Anal. Calcd for C₂₃H₃₀N₄O₂S: C, 64.76; H, 7.09; N, 13.13; S, 7.52. FoundC, 64.96; H, 7.01; N, 13.47; S, 7.38.

Example 139 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N-benzyl-N′,N′-dimethyl-1,2-ethanediamino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl-1,3,4-oxadiazole (144mg, 0.42 mmol), N′-benzyl-N,N-dimethylethylenediamine (0.16 mL, 0.85mmol) and glacial acetic acid (0.025 mL, 0.44 mmol) in1,2-dichloroethane (3.0 mL) was stirred under nitrogen at roomtemperature. Sodium triacetoxyborohydride (135 mg, 0.64 mmol) was addedand the reaction stirred for 4 h. The mixture was then diluted withmethylene chloride (5 mL), washed with 2 N NaOH (10 mL), dried (MgSO₄),filtered and concentrated to yield 0.31 g of a pale yellow oil. Thismaterial was purified by preparative TLC [90% methylene chloride/5%methanol/5% (2.0 M ammonia/methanol)] to yield 101 mg (47%) of a whitesolid.

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz), 7.32 (m,5H), 7.27 (m, 2H), 6.92 (m, 1H), 6.87 (d, 2H, J=8 Hz), 4.19 (t, 2H, J=12Hz), 4.03 (s, 2H), 3.64 (s, 2H), 3.60 (s, 2H), 3.03 (t, 2H, J=12 Hz),2.58 (dd, 2H, J=7 and 8 Hz), 2.45 (dd, 2H, J=7 and 8 Hz), 2.22 (s, 6H).IR (Kr, cm⁻¹) 3435, 3028, 2970, 2931, 2877, 2793, 1597, 1557, 1496,1458, 1418, 1364, 1295, 1239, 1170, 1119, 1077, 1018, 971, 836, 746,694. MS (ES+) m/e 503 (M+1). Anal. Calcd for C₂₉H₃₄N₄O₂S: C, 69.29; H,6.82; N, 11.15; S, 6.38. Found C, 68.96; H, 6.90; N, 11.15; S, 6.27.

Example 140 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N,N′,N′-trimethyl-1,2-propanediamino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(144 mg, 0.42 mmol), N,N,N′-trimethyl-1,3-propanediamine (0.125 mL, 0.85mmol) and glacial acetic acid (0.025 mL, 0.44 mmol) in1,2-dichloro-ethane (3.0 mL) was stirred under nitrogen at roomtemperature. Sodium triacetoxyborohydride (135 mg, 0.64 mmol) was addedand the reaction stirred for 3 h. The mixture was then diluted withmethylene chloride (5 mL), washed with 2 N NaOH (10 mL), dried (MgSO₄),filtered and concentrated to yield 0.24 g of a pale yellow oil. Thismaterial was purified by preparative TLC [90% methylene chloride/5%methanol/5% (2.0 M ammonia/methanol)] to yield 87 mg (47%) of acolorless oil.

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 7.25 (m,2H), 6.92 (m, 1H), 6.87 (d, 2H, J=9 Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s,2H), 3.52 (s, 2H), 3.03 (t, 2H, J=12 Hz), 2.40 (dd, 2H, J=7 and 8 Hz),2.31 (dd, 2H, J=7 and 8 Hz), 2.23 (s, 6H), 2.18 (s, 3H), 1.71 (m, 2H).IR (film, cm⁻¹) 3402, 1595, 1491, 1239, 755, 730. MS (ES+) m/e 442(M+1). Anal. Calcd for C₂₄H₃₂N₄O₂S: C, 65.42; H, 7.32; N, 12.72; S,7.28. Found C, 65.68; H, 7.58; N, 12.61; S, 7.23.

Example 141 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(N-benzyl-N′,N′-dimethyl-1,3-propanediamino)phenyl]-1,3,4-oxadiazole

A solution of2-{[(2-Phenoxyethyl)thio]methyl}-5-{-[(N′,N′-dimethyl-1,3-propanediamino)methyl]phenyl}-1,3,4-oxadiazole(110 mg, 0.26 mmol), benzaldehyde (0.03 mL, 0.28 mmol) and glacialacetic acid (0.015 mL, 0.26 mmol) in 1,2-dichloro-ethane (3.0 mL) wasstirred under nitrogen at room temperature. Sodium triacetoxyborohydride(82 mg, 0.39 mmol) was added and the reaction stirred for 8 h. Themixture was then diluted with methylene chloride (5 mL), washed with 2 NNaOH (10 mL), dried (MgSO₄), filtered and concentrated to yield 0.15 gof a pale yellow oil. This material was purified by preparative TLC [90%methylene chloride/5% methanol/5% (2.0 M ammonia/methanol)]to yield 52mg (39%) of a white solid.

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.47 (d, 2H, J=8 Hz), 7.32 (m,5H), 7.28 (m, 2H), 6.92 (m, 1H), 6.87 (d, 2H, J=8 Hz), 4.18 (t, 2H, J=12Hz), 4.03 (s, 2H), 3.59 (s, 2H), 3.56 (s, 2H), 3.03 (t, 2H, J=312 Hz),2.45 (dd, 2H, J=7 and 8 Hz), 2.24 (m, 2H), 2.17 (s, 6H), 1.68 (m, 2H).IR (KBr, cm⁻¹) 3434, 3026, 2934, 2874, 2785, 2357, 1597, 1558, 1495,1456, 1419, 1369, 1297, 1239, 1173, 1118, 1075, 1020, 967, 830, 745,693. MS (ES+) m/e 518 (M+1). Anal. Calcd for C₃₀H₃₆N₄O₂S: C, 69.74; H,7.02; N, 10.84; S, 6.21. Found C, 69.65; H, 6.96; N, 10.67; S, 6.39.

Example 142 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N,N-bis-(3-N′,N′-dimethyl)propyl)amino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(163 mg, 0.48 mmol), 3,3′-iminobis-(N,N-dimethylpropylamine) (0.22 mL,0.99 mmol) and glacial acetic acid (0.03 mL, 0.52 mmol) in1,2-dichloroethane (4.0 mL) was stirred under nitrogen at roomtemperature. Sodium triacetoxyborohydride (153 mg, 0.72 mmol) was addedand the reaction stirred for 16 h. The mixture was then diluted withmethylene chloride (10 mL), washed with 2 N NaOH (10 mL), dried (MgSO₄),filtered and concentrated to yield 0.35 g of a pale yellow oil. Half ofthis material was purified by preparative TLC [90% methylene chloride/5%methanol/5% (2.0 M ammonia-methanol)]to yield 84 mg (34%) of a whitesolid.

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 7.25 (m,2H), 6.90 (m, 1H), 6.88 (d, 2H, J=8 Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s,2H), 3.59 (s, 2H), 3.04 (t, 2H, J=12 Hz), 2.44 (t, 4H, J=15 Hz), 2.26(t, 4H, J=15 Hz), 2.20 (s, 12H), 1.63 (m, 4H). IR (KBr, cm⁻¹) 3430,2939, 2889, 2863, 2812, 2770, 2720, 1599, 1562, 1497, 1461, 1380, 1297,1242, 1173, 1082, 1027, 826, 751, 691. MS (ES+) m/e 513 (M+1). Anal.Calcd for C₂₈H₄₁N₅O₂S: C, 65.72; H, 8.08; N, 13.68; S, 6.26. Found C,65.19; H, 8.10; N, 13.39; S, 6.28.

Example 143 Preparation of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(N′,N′-dimethyl-1,2-ethanediamino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(340 mg, 1.0 mmol), N,N-dimethyl-1,2-ethylenediamine (0.22 mL, 2.0 mmol)and glacial acetic acid (0.06 mL, 1.0 mmol) in 1,2-dichloroethane (6.0mL) was stirred under nitrogen at room temperature. Sodiumtriacetoxyborohydride (320 mg, 1.5 mmol) was added and the reactionstirred for 16 h. The mixture was then diluted with methylene chloride(10 mL), washed with 2 N NaOH (10 mL), dried (MgSO₄), filtered andconcentrated to yield 0.43 g of a pale yellow oil. This material waspurified by preparative TLC [90% methylene chloride/5% methanol/5% (2.0M ammonia/methanol)] to yield 154 mg (37%) of a white solid.

¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8 Hz), 7.45 (d, 2H, J=8 Hz), 7.25 (m,2H), 6.93 (m, 1H), 6.87 (d, 2H, J=8 Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s,2H), 3.86 (s, 21), 3.04 (t, 2H, J=12 Hz), 2.67 (t, 2H, J=12 Hz), 2.43(t, 2H, J=12 Hz), 2.20 (s, 6H). IR (KBr, cm⁻¹) 3423, 3318, 2970, 2928,2856, 2812, 2781, 1595, 1560, 1492, 1461, 1418, 1237, 1079, 1019, 818,757, 697. MS (ES+) m/e 414 (M+1). Anal. Calcd for C₂₂H₂₈N₄O₂S: C, 64.05;H, 6.84; N, 13.58; S, 7.77. Found C, 64.32; H, 6.24; N, 13.52; S, 7.60.

Example 144 Preparation of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[((1-benzyl-2-(N,N-dimethylamino)ethyl)amino)methyl]phenyl}-1,3,4-oxadiazole

a) (+)-N-(tert-Butyloxycarbonyl)-2-benzylaziridine

A solution of (+)-2-amino-3-phenylpropanol (6 g, 40 mmol) and di-t-butyldicarbonate (9.53 g, 44 mmol) in isopropyl alcohol (20 mL) and1,4-dioxane (40 mL) was stirred at room temperature for 4 h. Thereaction was concentrated and vacuum dried. This material,p-toluenesulfonyl chloride (9.2 g, 48 mmol) and potassium hydroxide (9.0g, 160 mmol) were stirred in ethyl ether (400 mL) at room temperaturefor 20 h. The mixture was then poured into ice water (400 mL). Theaqueous material was extracted with ethyl ether (300 mL) and thecombined organic fractions were dried (MgSO₄), filtered and concentratedto yield 9.0 g (97%) of a colorless oil.

¹H NMR (CDCl₃) δ 7.25 (m, 5H), 2.95 (m, 1H), 2.60 (m, 2H), 2.33 (m, 1H),2.00 (m, 1H), 1.42 (s, 9H). MS (ES+) m/e 134 (M+1-Boc).

b) (+)-N,N-Dimethyl-2-amino-3-phenylpropylamine

A solution of (+)-N-boc-2-benzylaziridine (3.0 g, 12.9 mmol) anddimethylamine (2.0 M in THF, 50 mL, 100 mmol) in anhydrous acetonitrile(20 mL) was split among three sealed tubes and refluxed for 20 h. Themixture was concentrated to yield 4.0 g of an orange oil. This materialwas dissolved in methanol (20 mL) and loaded onto a column containingBio-Rad 50W-X2 cationic exchange resin (60 g, pre-washed with 800 mL ofmethanol). The column was washed with methanol (800 mL) and methylenechloride (200 mL). The product was eluted with 2.0 N ammonia/methanol(400 mL) and concentrated to yield 3.2 g (89%) of an orange oil. Thisproduct was dissolved in 25% trifluoroacetic acid/methylene chloride (40mL) and stirred at room temperature for 16 h. The reaction wasconcentrated, dissolved in methanol (5 mL) and added dropwise to 2N HClin ethyl ether to generate a solid hydrochloride salt, but the resultwas a thick oil which would not crystallize. This mixture was thenconcentrated, dissolved in methanol (20 mL) and loaded onto anothercolumn of 50W-X2 resin (50 g), described above. The product was,isolated (1.86 g, 91% yield) as a yellow oil.

¹H NMR (CDCl₃) δ 7.17–7.30 (m, 5H), 3.12 (m, 1H), 2.72 (dd, 1H, J=5 and9 Hz), 2.45 (dd, 1H, J=5 and 9 Hz), 2.21 (s, 6H), 2.14 (m, 2H). MS (ES+)m/e 179 (M+1).

c)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[((1-benzyl-2-(N,N-dimethylamino)ethyl)amino)methyl]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(205 mg, 0.6 mmol), (+)-N,N-dimethyl-2-amino-3-phenylpropylaminehydrochloride salt (430 mg, 2.0 mmol) and glacial acetic acid (0.06 mL,1 mmol) in 1,2-dichloroethane (8 mL) was stirred under nitrogen at roomtemperature. Sodium triacetoxyborohydride (191 mg, 0.9 mmol) was addedand the reaction stirred for 2 h. The mixture was diluted with methylenechloride (10 mL), extracted with 2 N NaOH (10 mL), dried (MgSO₄),filtered and concentrated to yield 483 mg of an orange oil. This oil waspurified by preparative TLC [90% methylene chloride/5% methanol/5% (2.0N ammonia in methanol)]to yield 98 mg (32%) of a solid.

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8 Hz), 7.36 (d, 2H, J=8 Hz), 7.25 (m,5H), 7.18 (m, 1H), 7.14 (d, 2H, J=8 Hz), 6.93 (dd, 1H, J=7 and 8 Hz),6.88 (d, 2H, J=9 Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s, 2H), 3.78 (dd, 2H,J=14 and 14 Hz), 3.04 (t, 2H, J=12 Hz), 2.82 (m, 1H), 2.61 (m, 1H), 2.29(m, 1H), 2.08 (s, 6H), 2.05 (m, 1H). IR (KBr, cm⁻¹) 3027, 2978, 2933,2885, 2853, 2816, 2777, 1599, 1562, 1495, 1454, 1359, 1289, 1244, 1167,1121, 1078, 1025, 976, 835, 803, 749, 696, 512. MS (ES+) m/e 503 (M+1).Anal. Calcd for C₂₉H₃₄N₄O₂S: C, 69.29; H, 6.82; N, 11.15; S, 6.38. FoundC, 69.65; H, 6.84; N, 10.90; S, 6.22.

Example 145 Preparation of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[4-(N,N-dimethylamino)-1-hydroxybutyl]phenyl}-1,3,4-oxadiazole

a)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-(1,3-dioxolan-2-yl)-1-hydroxypropyl]phenyl}-1,3,4-oxadiazole

A mixture of 1,2-dibromoethane (0.09 mL, 1 mmol) and magnesium turnings(243 mg, 10 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled in anice water bath under nitrogen. A solution of2-(2-bromoethyl)-1,3-dioxolane (1.5 mL, 12.5 mmol) in tetrahydrofuran (1mL) was added dropwise and the mixture stirred in the cooling bath for10 min. The mixture was then stirred at room temperature until themagnesium had gone into solution (50 min). After cooling in a dryice/isopropanol bath, a solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole intetrahydrofuran (5 mL) was added dropwise and stirred for 2 h in thecooling bath. The reaction was quenched with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (3×20 mL). The organicmaterial was extracted with brine (25 mL), dried (MgSO₄), filtered andconcentrated to yield 1.56 g of a pale yellow oil. This oil was purifiedby silica gel (50% ethyl acetate/hexanes) to yield 781 mg (88%) of anoil.

¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=8 Hz), 7.47 (d, 2H, J=8 Hz), 7.24 (m,1H), 6.93 (dd, 1H, J=6 and 7 Hz), 6.87 (d, 2H, J=7 Hz), 4.91 (t, 1H, J=8Hz), 4.81 (m, 1H), 4.19 (t, 2H, J=12 Hz), 4.03 (s, 2H), 3.95 (m, 2H),3.86 (m, 2H), 3.03 (t, 2H, J=12 Hz), 2.85 (d, 1H, J=4 Hz), 1.89 (m, 2H),1.82 (m, 2H). MS (ES+) m/e 443 (M+1).

b)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(5-hydroxy-2,3,4,5-tetrahydrofuran-2-yl)phenyl]-1,3,4-oxadiazole,mixture of cis- and trans-isomers

A mixture of(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-(1,3-dioxolan-2-yl)-1-hydroxypropyl]phenyl}-1,3,4-oxadiazole(658 mg, 1.49 mmol) and iron (III) chloride hexahydrate (1.41 g, 5.21mmol) in methylene chloride (30 mL) was stirred at room temperature for1 h. The reaction was quenched with saturated aqueous sodium bicarbonate(25 mL) and extracted with methylene chloride (3×25 mL). The organicmaterial was washed with brine (4×20 mL), dried (MgSO₄), filtered andconcentrated to yield 498 mg of an orange oil. This oil was purified bypreparative TLC (50% ethyl acetate/hexanes to yield 103 mg (17%) of acolorless oil.

¹H NMR (CDCl₃) δ 7.99 (d, 2H, J=8 Hz), 7.52 (d, 1H, J=8 Hz), 7.42 (d,1H, J=8 Hz), 7.24 (m, 1H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=7Hz), [cis/trans protons: 5.79 (m, 0.5H), 5.66 (m, 0.5H), 5.29 (m, 0.5H),5.06 (m, 0.5H)], 4.19 (t, 2H, J=12 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=12Hz), 2.73 (br s, 0.5H), 2.56 (br s, 0.5H), 2.33–2.54 (m, 1H), 1.96–2.18(m, 2H), 1.76 (m, 1H). MS (ES+) m/e 399 (M+1).

c)(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[4-(N,N-dimethylamino)-1-hydroxybutyl]phenyl}-1,3,4-oxadiazole

A solution of cis- andtrans-(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(5-hydroxy-2,3,4,5-tetrahydrofuran-2-yl)phenyl]-1,3,4-oxadiazole(100 mg, 0.25 mmol), dimethylamine (2.0 M in THF, 2 mL, 4 mmol) andglacial acetic acid (0.02 mL, 0.35 mmol) in 1,2-dichloroethane wasstirred under nitrogen. Sodium triacetoxyborohydride (160 mg, 0.76 mmol)was added and the reaction stirred at room temperature for 16 h. Themixture was diluted with methylene chloride (10 mL) and extracted with2N NaOH (10 mL), dried (MgSO₄), filtered and concentrated to yield 210mg of an orange oil. This oil was purified by preparative TLC [90%methylene chloride/5% methanol/5% (2.0 N ammonia in methanol)]to yield35 mg (33%) of a white solid.

¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8 Hz), 7.51 (d, 2H, J=8 Hz), 7.24 (m,2H), 6.92 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz), 4.72 (d, 1H, J=6Hz), 4.19 (t, 2H, J=12 Hz), 4.03 (s, 2H), 3.47 (s, 1H), 3.03 (t, 2H,J=12 Hz), 2.42 (m, 2H), 2.32 (s, 6H), 1.99 (m, 2H), 1.75–1.86 (m, 2H).IR (KBr, cm⁻¹) 3407, 3167, 3093, 3058, 2916, 2868, 2794, 2734, 1594,1562, 1493, 1464, 1414, 1293, 1236, 1171, 1078, 1013, 838, 755, 696. MS(ES+) m/e 428 (M+1). Anal. Calcd for C₂₃H₂₉N₃O₃S: C, 64.61; H, 6.84; N,9.83; S, 7.50. Found C, 64.66; H, 6.41; N, 9.31; S, 7.30.

Example 146 Preparation of(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-amino-3-benzylpropen-1-yl)phenyl]-1,3,4-oxadiazole

a)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-3-(tert-butoxycarbonylamino)propen-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-formylphenyl)-1,3,4-oxadiazole(510 mg, 1.5 mmol), 1-(ter-butoxycarbonyl)-2-benzylaziridine (R- orS-isomer, 933 mg, 4 mmol), and triphenylphosphine (1.05 g, 4 mmol) in2-propanol (2 mL) was stirred in a sealed tube at 95˜100° C. (bathtemperature) for 3 days. The reaction mixture was concentrated andpurified by chromatography (silica gel, EtOAc/hexanes 1:5). The isolatedproduct was triturated from methylene chloride and haxanes to give pureE-olefines: R-isomer (210 mg, 25%), S-isomer (241 mg, 29%).

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.4 Hz), 7.40 (d, 2H, J=8.1 Hz),7.18˜7.31 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.6 Hz) 6.46(d, 1H, J=16.1 Hz), 6.25 (dd, 1H, J=16.1, 5.6 Hz), 4.52˜4.65 (m, 2H),4.19 (t, 2H, J=6.1 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=6.1 Hz), 2.93 (d,2H, J=6.3 Hz), 1.40 (s, 9H). IR (KBr, cm⁻¹) 3014, 2949, 2796, 2251,1688, 1598, 1553, 1326, 1243, 926, 744, 651. MS (ES+) m/e 558 (M+1).Anal. Calcd for C₃₂H₃₅N₃O₄S: C, 68.92; H, 6.33; N, 7.53; S, 5.75. FoundR-isomer, C, 68.84; H, 6.35; N, 7.44; S, 5.82; S-isomer, C, 68.88; H,6.27; N, 7.36; S, 5.79.

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-amino-3-benzylpropen-1-yl)phenyl]-1,3,4-oxadiazole

Trifluoroacetic acid (0.5 mL) was added to a solution of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-3-(tert-butoxycarbonylamino)propen-1-yl]phenyl}-1,3,4-oxadiazole(139 mg, 0.25 mmol) in methylene chloride (2 mL). The resultant mixturewas stirred at room temperature overnight, concentrated, and partitionedbetween methylene chloride (20 mL) and 2 M NaOH (5 mL). The organiclayer was dried (MgSO₄), concentrated and purified by chromatography(silica gel, 5% methanol/methylene chloride) to give a pale yellowsolid: R-isomer, 87 mg, 76%; S-isomer, 80 mg, 70%.

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.5 Hz), 7.44 (d, 2H, J=8.4 Hz),7.21˜7.32 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz) 6.53(d, 1H, J=16.1 Hz), 6.36 (dd, 1H, J=15.8, 6.6 Hz), 4.19 (t, 2H, J=6.2Hz), 4.03 (s, 2H), 3.81 (m, 11H), 3.04 (t, 2H, J=6.2 Hz), 2.93 (dd, 2H,J=13.3, 5.3 Hz), 2.73 (dd, 1H, J=13.3, 8.2 Hz). IR (KBr, cm⁻¹) 3028,2935, 2866, 2830, 1601, 1560, 1494, 1464, 1221, 1050, 915, 733, 700. MS(ES+) m/e 458 (M+1). Anal. Calcd for C₂₇H₂₇N₃O₂S: C, 70.87; H, 5.95; N,9.18; S, 7.01. Found R-isomer, C, 70.52; H, 5.93; N, 9.03; S, 7.28;S-isomer, C, 70.94; H, 5.88; N, 9.12; S, 7.00.

Example 147 Preparation of(E)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-3-(2-(N,N-dimethylamino)acetamido)propen-1-yl]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(3-amino-3-benzylpropen-1-yl)phenyl]-1,3,4-oxadiazole(46 mg, 0.1 mmol) and N,N-dimethylglycine (20 mg, 0.2 mmol) in pyridine(1 mL), under nitrogen, was cooled to −10˜−5° C. (ice-salt bath) andphosphorus oxychloride (0.05 mL, 0.5 mmol) was added. The mixture wasstirred at −10˜−5° C. for 90 min and water (2 mL), followed by ethylacetate (25 mL), was added. The mixture was washed with 2 M NaOH (2×5mL), water (3×10 mL), and brine (10 mL), dried MgSO₄), and concentrated.The residue was co-evaporated with toluene (20 mL) under reducedpressure and purified by preparative TLC (silica gel, 5%methanol/methylene chloride) to give a white solid: R-isomer, 34 mg,62%; S-isomer, 35 mg, 65%.

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.5 Hz), 7.41 (d, 2H, J=8.5 Hz),7.19˜7.30 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7 Hz) 6.49(d, 1H, J=16.1 Hz), 6.29 (dd, 1H, J=16.1, 6.2 Hz), 4.95 (m, 1H), 4.19(t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=6.2 Hz), 2.82˜3.06 (m,4H), 2.18 (s, 6H). IR (KBr, cm⁻¹) 3402, 3025, 2958, 2855, 2799, 2776,1688, 1597, 1550, 1494, 1481, 1239, 1058, 980, 751. MS (ES+) m/e 543(M+1). Anal. Calcd for C₃₁H₃₄N₄O₃S: C, 68.61; H, 6.31; N, 10.32; S,5.91. Found R-isomer C, 68.88; H, 6.27; N, 10.25; S, 5.74; S-isomer C,68.78; H, 6.22; N, 10.24; S, 5.92.

Example 148 Preparation of(R)-(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[3-benzyl-3-(N,N-dimethylamino)propen-1-yl]phenyl}-1,3,4-oxadiazole

A solution containing(R)-(E)-2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(3-benzyl-3-aminopropen-1-yl)phenyl]-1,3,4-oxadiazole(258 mg, 0.56 mmol) and paraformaldehyde (170 mg, 5.6 mmol) in methanol(6.0 mL) was refluxed for 3 h. The mixture was cooled and sodiumcyanoborohydride (107 mg, 1.70 mmol) was added; the reaction stirred atroom temperature for 2 h. The mixture was diluted with water (10 mL) andthe methanol was removed in vacuo. Saturated aqueous sodium bicarbonate(10 mL) was added and the mixture was extracted with methylene chloride(3×15 mL). The organic material was dried (MgSO₄), filtered andconcentrated to yield 355 mg of an orange oil. This oil was purified bypreparative TLC (10% methanol/methylene chloride) to yield 163 mg (59%)of a pale yellow oil.

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=9 Hz), 7.35 (d, 2H, J=8 Hz), 7.24 (m,5H), 7.13 (m, 2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz),4.18 (t, 2H, J=12 Hz), 4.03 (s, 2H), 3.20 (m, 1H), 3.11 (dd, 2H, J=4 and9 Hz), 3.03 (t, 2H, J=12 Hz), 2.75 (dd, 2H, J=4 and 9 Hz), 2.37 (s, 6H).IR (film, cm⁻¹) 3030, 2935, 2865, 2823, 2779, 1599, 1557, 1494, 1462,1239, 1078, 1031, 910, 733, 699. MS (ES+) m/e 486 (M+1). Anal. Calcd forC₂₉H₃₁N₃O₂S: C, 71.72; H, 6.43; N, 8.65; S, 6.60. Found C, 71.26; H,6.21; N, 8.54; S, 6.53.

Example 149 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

a) 2-{[(2-Phenoxyethyl)thio]methyl}-5-(4-nitrophenyl)-1,3,4-oxadiazole

A mixture of 4-nitrobenzoic hydrazide (4.35 g, 24 mmol),2-(2-phenoxyethylthio)acetic acid (4.25 g, 20 mmol), and(4-N,N-dimethylaminophenyl)diphenylphosphine (18.32 g, 60 mmol) inacetonitrile (200 mL) was stirred and cooled with an ice bath. A mixtureof triethylamine (10.12 g, 100 mmol) and carbon tetrachloride (15.38 g,100 mmol) was added dropwise over 5 min. The cooling was maintained foradditional 10 min and removed, and the mixture was allowed to stirovernight. The resultant mixture was concentrated to approximately halfthe original volume. Diethyl ether (50 mL) and 2 N HCl (300 mL) wereadded and the mixture was swirled until all solid was dispersed. Thesolid was collected by filtration and transferred to a beaker. 2 M HCl(300 mL) was added and the mixture was stirred until finely dispersed.The solid was collected by filtration and similarly washed again with 2MHCl (300 mL), followed by water (300 mL). The solid was air-dried togive a light tan powder (5.01 g, 70%).

¹H NMR (CDCl₃) δ 8.33 (d, 2H, J=9.2 Hz), 8.18 (d, 2H, J=9.2 Hz),7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.86 (d, 2H, J=7.7 Hz), 4.20(t, 2H, J=6.1 Hz), 4.08 (s, 2H), 3.05 (t, 2H, J=6.0 Hz). MS (ES+) m/e358. (M+1).

b) 2-{[(2-Phenoxyethyl)thio]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-nitrophenyl)-1,3,4-oxadiazole(3.57 g, 10 mmol), indium powder (8.03 g, 70 mmol), ethanol (40 mL), andsat. aqueous ammonium chloride (12 mL), added in that order, was stirredunder reflux for 2 h. 2 M NaOH (50 mL) was added and the mixture wasfiltered over Celite. The reaction flask and Celite pad were washed withmethylene chloride (50 mL). The combined filtrates were evaporated toremove dichloromethane and most ethanol. The precipitate was collectedby filtration, washed with water (15 mL) and ethanol (3 mL), andair-dried to give the desired product (yellow to orange solid, 75˜80%yield).

¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.4 Hz), 7.22˜7.26 (m, 2H), 6.92 (t, 1H,J=7.3 Hz), 6.87 (d, 2H, J=8.1 Hz), 6.69 (d, 2H, J=8.8 Hz), 4.17 (t, 2H,J=6.2 Hz), 3.99 (s, 2H), 3.02 (t, 2H, J=6.2 Hz). MS (ES+) m/e 328 (M+1).

c)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

To a suspension of 4-(N,N-dimethylamino)butyric acid hydrochloride (1.67g, 10 mmol) in N,N-dimethylformamide (0.5 mL) and methylene chloride (50mL) was added oxalyl chloride (1.48 mL, 17 mmol) dropwise over a periodof 10 min. The mixture was stirred at room temperature for 2 h andevaporated under reduced pressure to remove methylene chloride andexcess oxalyl chloride. The resultant white solid was dissolved inmethylene chloride (5 mL) and added dropwise over 2 min to a solution of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole (982mg, 3 mmol), 4-(N,N-dimethylamino)pyridine (183 mg, 1.5 mmol), andtriethylamine (1.01 g, 10 mmol) in methylene chloride (25 mL) at 0° C.After 20 min the cooling bath was removed, and the mixture was allowedto stir overnight, washed with 2 M NaOH (4×15 mL), dried (MgSO₄), andconcentrated. The residue was dissolved in methanol (30 mL), dilutedwith water (5 mL), and concentrated under reduced pressure to removemost methanol. The precipitate was collected by filtration, washed withwater (5 mL), redissolved in methylene chloride (30 mL), washed withwater (15 mL), dried (MgSO₄), and concentrated. The residue wastriturated from methylene chloride and hexanes to give an off-whitesolid (839 mg, 64%).

¹H NMR (CDCl₃) δ 10.60 (s, 1H), 7.94 (d, 2H, J=8.4 Hz), 7.65 (d, 2H,J=8.8 Hz), 7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.7Hz), 4.18 (t, 2H, J=6.2 Hz), 4.02 (s, 2H), 3.03 (t, 2H, J=6.0 Hz),2.49˜2.57 (m, 4H), 2.36 (s, 6H), 1.87˜1.91 (m, 2H). IR (KBr, cm⁻¹) 3494,3456, 3313, 2939, 1666, 1605, 1499, 1465, 1243, 1177, 1035, 760. MS(ES+) m/e 441 (M+1). Anal. Calcd for C₂₃H₂₈N₄O₃S: C, 62.70; H, 6.41; N,12.72; S, 7.28. Found C, 62.59; H, 6.51; N, 12.69; S, 7.23.

Example 150 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-(N,N′,N′-trimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

a)2-{[92-Phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole

A suspension of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole(1.636 g, 5 mmol) in toluene (30 mL) was heated to approximately 50° C.and chloroacetic chloride (1.636 mL, 20 mmol) was added. The mixture wasstirred under reflux for 4 h and allowed to cool to room temperature.The solid was collected by filtration, washed with hexanes and air-driedto give the desired product (1.61 g, 80%).

¹H NMR (CDCl₃) δ 8.8 (s, 1H), 8.01 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6Hz), 7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.4 Hz), 6.87 (d, 2H, J=7.8 Hz),4.21 (s, 2H), 4.19 (t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.04 (t, 2H, J=6.2Hz). MS (ES+) m/e 404 (M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-(N,N′,N′-trimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]1,3,4-oxadiazole(100 mg, 0.25 mmol) and N,N,N′-trimethylethylenediamine (1.5 mL) wasstirred at room temperature overnight and excessN,N,N′-trimethylethylenediamine was evaporated under vacuum. The residuewas purified by preparative TLC (silica gel, 10% methanol/methylenechloride) to give a pale yellow oil (100 mg, 85%).

¹H NMR (CDCl₃) δ 10.41 (s, 1H), 7.96 (d, 2H, J=8.5 Hz), 7.79 (m, 2H),7.23˜7.27 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.88 (d, 2H, J=7.6 Hz), 4.19(t, 2H, J=6.0 Hz), 4.02 (s, 2H), 3.20 (s, 2H), 3.03 (t, 2H, J=6.0 Hz),2.60 (m, 2H), 2.44 (s, 6H), 2.27 (m, 5H). IR (film, cm⁻¹) 3458, 3321,2940, 1669, 1602, 1501, 1411, 1257, 1181, 753. MS (ES+) m/e 468 (M+1).Anal. Calcd for C₂₅H₃₃N₅O₂S: C, 64.21; H, 7.11; N, 14.98; S, 6.86. FoundC, 64.10; H, 7.06; N, 14.79; S, 6.88.

Example 151 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole(50 mg, 0.12 mmol) and N,N-dimethylethylenediamine (1 mL) was stirred atroom temperature overnight and excess N,N-dimethylethylenediamine wasevaporated under vacuum. The residue was purified by preparative TLC(silica gel, 10% methanol/methylene chloride) to give a pale yellow oil(28 mg, 51%).

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.7 Hz), 7.79 (d, 2H, J=8.8 Hz),7.22˜7.26 (m, 2H), 6.92 (t, 1H, J=7.7 Hz), 6.87 (d, 2H, J=7.7 Hz), 4.18(t, 2H, J=6.2 Hz), 4.02 (s, 2H), 3.41 (s, 2H), 3.04 (s, 1H), 3.03 (t,2H, J=5.9 Hz), 2.79 (t, 2H, J=5.6 Hz), 2.50 (t, 2H, J=5.6 Hz), 2.31 (s,6H). IR (film, cm⁻¹) 3464, 3327, 2959, 1669, 1604, 1521, 1260, 1134,757. MS (ES+) m/e 454 (M+1). Anal. Calcd for C₂₄H₃₁N₅O₂S: C, 63.55; H,6.89; N, 15.44; S, 7.07. Found C, 63.75; H, 6.91; N, 15.28; S, 7.26.

Example 152 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-(N-benzyl-N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole(202 mg, 0.5 mmol) and N,N-dimethyl-N′-benzylethylenediamine (1.34 g,7.5 mmol) was stirred at 80˜90° C. overnight and excessN,N-dimethyl-N′-benzylethylenediamine was evaporated under vacuum. Theresidue was purified by preparative TLC (silica gel, 10%methanol/methylene chloride) to give a pale yellow oil (168 mg, 62%).

¹H NMR (CDCl₃) δ 10.75 (s, 1H), 7.96 (d, 2H, J=8.4 Hz), 7.72 (d, 2H,J=8.3 Hz), 7.24˜7.31 (m, 7H), 6.93 (t, 1H, J=7.5 Hz), 6.88 (d, 2H, J=8.0Hz), 4.19 (t, 2H, J=6.0 Hz), 4.03 (s, 2H), 3.75 (s, 2H), 3.28 (s, 2H),3.04 (t, 2H, J=6.0 Hz), 2.70 (t, 2H, J=5.4 Hz), 2.33˜2.42 (m, 2H), 2.17(s, 6H). IR (film, cm⁻¹) 3455, 3330, 2946, 1670, 1606, 1500, 1420, 1301,1256, 1177, 758. MS (ES+) m/e 544 (M+1). Anal. Calcd for C₃₁H₃₇N₅O₂S: C,68.48; H, 6.86; N, 12.88; S, 5.90. Found C, 68.53; H, 6.63; N, 12.71; S,5.82.

Example 153 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-((2-(N,N-dimethylamino)ethoxy)acetamido]phenyl}-1,3,4-oxadiazole

Sodium hydride (60% suspension in oil, 64 mg, 1.6 mmol) was washed withtetrahydrofuran (10 mL), suspended in N,N-dimethylformamide (15 mL) andcooled to 0° C. N,N-dimethylethanolamine (171 mg, 1.92 mmol) was addeddropwise over 2 min with stirring, and the mixture was allowed to warmto room temperature and stir for 30 min.2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole(130 mg, 0.32 mmol) was added and stirring was continued for 18 h. Thereaction mixture was poured into water (40 mL) and extracted with ethylacetate (4×15 mL). The combined ethyl acetate extracts were washed withwater (2×15 mL) and brine (20 mL), dried (MgSO₄), and concentrated. Theresidue was purified by chromatography (silica gel, 10%methanol/methylene chloride) to give a colorless oil (77 mg, 53%).

¹H NMR (CDCl₃) δ 10.25 (s, 1H), 7.97 (d, 2H, J=8.8 Hz), 7.78 (d, 2H,J=8.4 Hz), 7.22˜7.27 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=7.6Hz), 4.19 (t, 2H, J=6.2 Hz), 4.11 (s, 2H), 4.02 (s, 2H), 3.69 (t, 2H,J=5.0 Hz), 3.03 (t, 2H, J=6.0 Hz), 2.60 (m, 2H), 2.36 (s, 6H). IR (film,cm⁻¹) 3470, 3334, 2934, 1669, 1599, 1498, 1412, 1248, 1182, 1036, 756.MS (ES+) m/e 457 (M+1). Anal. Calcd for C₂₃H₂₈N₄O₄S: C, 60.51; H, 6.18;N, 12.27; S, 7.02. Found C, 60.37; H, 6.10; N, 12.17; S, 6.94.

Example 154 Preparation of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[2-(2-(N,N-dimethylamino)-1-methylethoxy)acetamido]phenyl}-1,3,4-oxadiazole

Sodium hydride (60% suspension in oil, 200 mg, 5 mmol) was washed withtetrahydrofuran (10 mL), suspended in N,N-dimethylformamide (5 mL) andcooled to 0° C. with stirring. 1-(N,N-diethylamino)-2-propanol (1.03 g,10 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, andstirring was continued for 10 min at 0° C. and 30 min at roomtemperature.2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole(202 mg, 0.5 mmol) was added and the resultant mixture was stirred atroom temperature for 2.5 h. The reaction mixture was diluted with ethylacetate (40 mL), washed with water (5×15 mL) and brine (15 mL), dried(MgSO₄), and concentrated. The residue was purified by chromatography(silica gel, 5% methanol/methylene chloride) to give a colorless oil(120 mg, 51%).

¹H NMR (CDCl₃) δ 10.83 (s, 1H), 7.97 (d, 2H, J=8.8 Hz), 7.73 (d, 2H,J=8.5 Hz), 7.22˜7.26 (m, 2H), 6.93 (t, 1H, J=7.7 Hz), 6.87 (d, 2H, J=7.6Hz), 4.23 (d, 1H, J=16.9 Hz), 4.19 (t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.95(d, 1H, J=16.9 Hz), 3.55 (m, 1H), 3.03 (t, 2H, J=6.2 Hz), 2.61 (t, 1H,J=11.5 Hz), 2.31 (s, 6H), 2.15 (m, 1H), 1.13 (d, 3H, J=5.8 Hz). IR(film, cm⁻¹) 3456, 3344, 2931, 1668, 1602, 1503, 1412, 1248, 1172, 1037,756. MS (ES+) m/e 471 (M+1). Anal. Calcd for C₂₄H₃₀N₄O₄S: C, 61.26; H,6.43; N, 11.91; S, 6.81. Found C, 61.23; H, 6.27; N, 11.79; S, 6.88.

Example 155 Preparation of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[2-(1-benzyl-2-(N,N-dimethylamino)ethoxy)acetamido]phenyl}-1,3,4-oxadiazole

a) (+)-1-Benzyl-2-(N,N-dimethylamino)ethanol

To a solution of 2,3-epoxypropylbenzene (1.34 g, 10 mmol) and lithiumperchlorate (1.17 g, 11 mmol) in acetonitrile (10 mL) was added 2 Mdimethylamine in tetrahydrofuran (5 mL 10 mmol). The resultant mixturewas stirred at room temperature overnight, diluted with ether (20 mL),washed with water (3×10 mL), dried (MgSO₄), and concentrated to give ayellow oil (1.61 g, 90%). This material was used in the next stepwithout further purification.

¹H NMR (CDCl₃) δ 7.16–7.28 (m, 5H), 3.84 (m, 1H), 2.78 (dd, 1H, J=13.5,7.1 Hz), 2.63 (dd, 1H, J=13.5, 5.6 Hz), 2.30 (dd, 1H, J=11.8, 10.4 Hz),2.22 (s, 6H), 2.15 (dd, 1H, J=12.1, 3.3 Hz). MS (ES+) m/e 181 (M+1).

b)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-(1-benzyl-2-(N,N-dimethylamino)ethoxy)acetamido]phenyl}-1,3,4-oxadiazole

Sodium hydride (60% suspension in oil, 80 mg, 2 mmol) was washed withtetrahydrofuran (10 mL), suspended in N,N-dimethylformamide (4 mL) andcooled to 0° C. with stirring. (+)-1-benzyl-2-(N,N-dimethylamino)ethanol(358 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was added dropwise, andstirring was continued for 10 min at 0° C. and 20 min at roomtemperature.2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(2-chloroacetamido)phenyl]-1,3,4-oxadiazole(202 mg, 0.5 mmol), followed by sodium iodide (149 mg, 1 mmol) was addedand the resultant mixture was stirred at room temperature for 3 h. Thereaction mixture was diluted with ethyl acetate (50 mL), washed withwater (4×25 mL) and brine (25 mL), dried (MgSO₄), and concentrated. Theresidue was purified by chromatography (silica gel, 5%methanol/methylene chloride) to give a colorless oil (114 mg, 42%).

¹H NMR (CDCl₃) δ 10.87 (s, 1H), 7.98 (d, 2H, J=8.8 Hz), 7.67 (d, 2H,J=8.8 Hz), 7.17˜7.32 (m, 7H), 6.92 (t, 1H, J=7.3 Hz), 6.87 (d, 2H, J=8.0Hz), 4.18 (t, 2H, J=6.2 Hz), 4.11 (d, 1H, J=17.2 Hz), 4.02 (s, 2H), 3.75(d, 1H, J=17.2 Hz), 3.66 (m, 1H), 3.03 (t, 2H, J=6.2 Hz), 2.76 (m, 2H),2.62 (dd, 1H, J=13.0, 10.4 Hz), 2.28 (m, 1H), 2.27 (s, 6H). IR (film,cm⁻¹) 3460, 3334, 2934, 1658, 1600, 1501, 1426, 1280, 1175, 1053, 761.MS (ES+) m/e 547 (M+1). Anal. Calcd for C₃₀H₃₄N₄O₄S: C, 65.91; H, 6.27;N, 10.25; S, 5.87. Found C, 66.04; H, 6.25; N, 10.31; S, 5.49.

Example 156 Preparation of2-{[(2-(4-Fluorophenoxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

a) Methyl 2-{[2-(tert-butyldimethylsilyloxy)ethyl]thio}acetate

A mixture of methyl thioglycolate (4.78 g, 45 mmol),2-bromoethoxy-tert-butyldimethylsilane (7.18 g, 30 mmol), and potassiumcarbonate (10.37 g, 75 mmol) in tetrahydrofuran (150 mL) was stirredunder reflux overnight. The resultant mixture was cooled to roomtemperature, diluted with ether (100 mL), washed with water (3×100 mL)and brine (100 mL), dried (MgSO₄), and concentrated to give a colorlessoil (7.85 g, 99%).

¹H NMR (CDCl₃) δ 3.78 (t, 2H, J=6.6 Hz), 3.71 (s, 3H), 3.27 (s, 2H),2.74 (t, 2H, J=6.6 Hz), 0.87 (s, 9H), 0.04 (s, 6H). MS (ES+) m/e 265(M+1).

b) 2-{[2-(tert-butyldimethylsilyloxy)ethyl]thio}acetic hydrazide

A mixture of methyl 2-{[2-(tert-butyldimethylsilyloxy)ethyl]thio}acetate(2.65 g, 10 mmol) and hydrazine monohydrate (5 g, 100 mmol) in ethanolwas stirred at room temperature for 2 h and concentrated. The residuewas taken up in ethyl acetate (50 mL), washed with water (5×20 mL),dried (MgSO₄), and concentrated to give a colorless oil (2.53 g, 96%).

¹H NMR (CDCl₃) δ 7.99 (br s, 1H), 3.85 (br s, 2H), 3.79 (t, 2H, J=6.0Hz), 3.29 (s, 2H), 2.68 (t, 2H, J=6.2 Hz), 0.88 (s, 9H), 0.06 (s, 6H).MS (ES+) m/e 265 (M+1).

c) 4-{[4-(N,N-Dimethylamino)butanoyl]amino}benzoic acid hydrochloride

A mixture of methyl 4-aminobenzoate (4.53 g, 30 mmol),4-(N,N-dimethylamino)butyric acid hydrochloride (6.71 g, 40 mmol),diisopropylcarbodiimide (5.05 g, 40 mmol), and 1-hydroxybenzotriazole(5.41 g, 40 mmol) in N,N-dimethylformamide (200 mL) was stirred at roomtemperature over the weekend. The reaction mixture was poured into water(600 mL), made basic with 2 M NaOH to pH ˜10, and extracted with ethylacetate (5×150 mL). The combined ethyl acetate extracts were washed with2 M NaOH (2×150 mL), dried (MgSO₄), and concentrated. The residue waspurified on a cation exchange column (Bio-Rad 50W-X2 resin) to givecolorless oil (6.18 g, 78%). This material (5.28 g, 20 mmol) wasdissolved in tetrahydrofuran (30 mL) and stirred with 2 M NaOH (50 mL,100 mmol) at room temperature overnight. Ether (30 mL) was added and thephases were separated. The aqueous layer was loaded to an anion exchangecolumn (Bio-Rad AG1-X2 resin). The column was eluted with water untilthe eluent became neutral, followed by 4 M HCl in dioxane to recover theproduct. Dioxane was evaporated. The resultant solid was washed withdioxane (250 mL) and methylene chloride (200 mL) to give the finalproduct (3.68, 64%).

¹H NMR (DMSO-d6) δ 10.40 (s, 1H), 10.0 (br s, 1H), 7.84 (d, 2H, J=8.8Hz), 7.68 (d, 2H, J=8.8 Hz), 3.03 (m, 2H), 2.72 (s, 6H), 2.45 (m, 2H),1.92 (m, 2H). MS (ES−) m/e 249 (M−1).

d)2-{[(2-(tert-Butyldimethylsilyloxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

To a stirred mixture of2-{[2-(tert-butyldimethylsilyloxy)ethyl]thio}acetic hydrazide (2.65 g,10 mmol), 4-{[4-(N,N-Dimethylamino)butanoyl]amino}benzoic acidhydrochloride (2.86 g, 10 mmol), and4-(N,N-dimethylaminophenyl)diphenylphosphine (9.16 g, 30 mmol) inacetonitrile (100 mL) at 0° C. was added slowly a solution oftriethylamine (6.07 g, 60 mmol) in carbon tetrachloride (7.69 g, 50mmol). The resultant mixture was stirred at room temperature overnightand concentrated. The residue was taken up in methylene chloride (150mL), washed with 2 M NaOH (2×50 mL), dried (MgSO₄), and concentrated.The residue was purified by chromatography (silica gel, 10%methanol/methylene chloride to 5% methanol and 5% 7 M methanolicammonia/methylene chloride) to give a pale yellow oil (1.79 g, 38%).

¹H NMR (CDCl₃) δ 10.16 (s, 1H), 7.97 (d, 2H, J=8.8 Hz), 7.87 (d, 2H,J=8.8 Hz), 3.96 (s, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.0 (t, 2H, J=5.6 Hz),2.75˜2.85 (m, 4H), 2.76 (s, 6H), 2.15˜2.19 (m, 2H), 0.87 (s, 9H), 0.05(s, 6H). IR (film, cm⁻¹) 3473, 3327, 2963, 1659, 1598, 1496, 1245, 1181,1088, 750. MS (ES+) m/e 479 (M+1). Anal. Calcd for C₂₃H₃₈N₄O₃SSi: C,57.71; H, 8.00; N, 11.70; S, 6.70. Found C, 57.57; H, 8.12; N, 11.52; S,6.91.

e)2-{[(2-hydroxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

2-{[(2-(tert-Butyldimethylsilyloxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(1.47 g, 3 mmol) was stirred in 2 M HCl (15 mL) until it appearedcompletely dissolved (˜30 min). The solution was washed with methylenechloride (3×10 mL), treated with 2 M NaOH to pH ˜11, and extracted withmethylene chloride (3×10 mL). The combined methylene chloride extractswere dried (MgSO₄) and concentrated to give a pale yellow solid (430 mg,39%).

¹H NMR (CDCl₃) δ 10.66 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 7.66 (d, 2H,J=7.8 Hz), 3.94 (s, 2H), 3.81 (t, 2H, J=5.9 Hz), 2.83 (t, 2H, J=5.6 Hz),2.49˜2.56 (m, 4H), 2.36 (s, 6H), 1.88 (m, 2H). IR (KBr, cm⁻¹) 3482,3330, 2957, 1661, 1603, 1501, 1411, 1168, 756. MS (ES+) m/e 365 (M+1).Anal. Calcd for C₁₇H₂₄N₄O₃S: C, 56.02; H, 6.64; N, 15.37; S, 8.80. FoundC, 56.16; H, 6.74; N, 15.38; S, 8.94.

f)2-{[(2-(4-Fluorophenoxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-hydroxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(130 mg, 0.36 mmol), 4-fluorophenol (161 mg, 1.44 mmol), andtriphenylphosphine (184 mg, 0.7 mmol) in tetrahydrofuran (6 mL) wascooled with an ice bath and diisopropyl azodicarboxylate (142 mg, 0.7mmol) in tetrahydrofuran (1 mL) was added dropwise. After 5 min thecooling bath was removed and the mixture was stirred at room temperatureovernight. The resultant mixture was diluted with ethyl acetate (10 mL),washed with 2 M NaOH (3×10 mL), dried (MgSO₄), and concentrated. Theresidue was purified by preparative TLC (silica gel, 5% methanol and 5%7 M methanolic ammonia in methylene chloride, twice developed) to give acolorless oil (151 mg, 92%).

¹H NMR (CDCl₃) δ 10.67 (s, 1H), 7.94 (d, 2H, J=8.8 Hz), 7.65 (d, 2H,J=8.4 Hz), 6.92 (t, 2H, J=8.6 Hz), 6.79˜6.82 (m, 2H), 4.13 (t, 2H, J=6.2Hz), 4.01 (s, 2H), 3.01 (t, 2H, J=6.2 Hz), 2.54 (t, 2H, J=6.4 Hz), 2.49(t, 2H, J=5.8 Hz), 2.35 (s, 6H), 1.84˜1.88 (m, 2H). IR (film, cm⁻¹)3456, 3322, 2957, 1657, 1600, 1446, 1382, 1215, 1177, 755. MS (ES+) m/e459 (M+1). Anal. Calcd for C₂₃H₂₇FN₄O₃S: C, 60.24; H, 5.93; N, 12.22; S,6.99. Found C, 60.13; H, 5.86; N, 12.36; S, 6.94.

Example 157 Preparation of2-{[(2-(4-Methoxyphenoxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-hydroxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(80 mg, 0.22 mmol), 4-methoxyphenol (109 mg, 0.88 mmol), andtriphenylphosphine (115 mg, 0.44 mmol) in tetrahydrofuran (8 mL) wascooled with an ice bath and diisopropyl azodicarboxylate (89 mg, 0.44mmol) in tetrahydrofuran (0.5 mL) was added dropwise. After 5 minutesthe cooling bath was removed and the mixture was stirred at roomtemperature overnight. The resultant mixture was diluted with ethylacetate (10 mL), washed with 2 M NaOH (3×5 mL), dried (MgSO₄), andconcentrated. The residue was purified by preparative TLC (silica gel,5% methanol and 5% 7 M methanolic ammonia in methylene chloride, twicedeveloped) to give a colorless oil (53 mg, 50%).

¹H NMR (CDCl₃) δ 10.63 (s, 1H), 7.94 (d, 2H, J=8.8 Hz), 7.66 (d, 2H,J=8.7 Hz), 6.81 (d, 2H, J=9.5 Hz), 6.78 (d, 2H, J=9.2 Hz), 4.13 (t, 2H,J=6.2 Hz), 4.01 (s, 2H), 3.73 (s, 3H), 3.0 (t, 2H, J=6.2 Hz), 2.49˜2.57(m, 4H), 2.36 (s, 6H), 1.83˜1.91 (m, 2H). IR (film, cm⁻¹) 3470, 3341,2955, 1661, 1606, 1500, 1438, 1388, 1237, 1176, 764. MS (ES+) m/e 471(M+1). Anal. Calcd for C₂₄H₃₀N₄O₄S: C, 61.26; H, 6.43; N, 11.91; S,6.81. Found C, 61.29; H, 6.45; N, 11.74; S, 6.73.

Example 158 Preparation of2-{[(2-(4-Benzoyloxyphenoxy)ethyl)thio]methyl-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

A solution of2-{[(2-hydroxyethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(80 mg, 0.22 mmol), 4-hydroxyphenyl benzoate (189 mg, 0.88 mmol), andtriphenylphosphine (116 mg, 0.44 mmol) in tetrahydrofuran (8 mL) wascooled with an ice bath and diisopropyl azodicarboxylate (89 mg, 0.44mmol) in tetrahydrofuran (0.5 mL) was added dropwise. After 5 min thecooling bath was removed and the mixture was stirred at room temperatureovernight. The resultant mixture was diluted with ethyl acetate (10 mL),washed with 2 M NaOH (3×5 mL), dried (MgSO₄), and concentrated. Theresidue was purified by preparative TLC (silica gel, 5% methanol and 5%7 M methanolic ammonia in methylene chloride, twice developed) to givecolorless oil (72 mg, 58%).

¹H NMR (CDCl₃) δ 10.55 (s, 1H), 8.17 (d, 2H, J=7.7 Hz), 7.95 (d, 2H,J=8.4 Hz), 7.67 (d, 2H, J=8.4 Hz), 7.61 (t, 1H, J=7.3 Hz), 7.48 (t, 2H,J=7.6 Hz), 7.09 (d, 2H, J=9.2 Hz), 6.91 (d, 2H, J=8.8 Hz), 4.19 (t, 2H,J=6.0 Hz), 4.02 (s, 2H), 3.05 (t, 2H, J=6.2 Hz), 2.46˜2.57 (m, 4H), 2.37(s, 6H), 1.86˜1.90 (m, 2H). IR (film, cm⁻¹) 3420, 3035, 2957, 2771,1763, 1660, 1601, 1499, 1423, 1215, 1170, 755. MS (ES+) m/e 561 (M+1).Anal. Calcd for C₃₀H₃₂N₄O₅S: C, 64.27; H, 5.75; N, 9.99; S, 5.72. FoundC, 64.40; H, 5.62; N, 10.03; S, 5.74.

Example 159 Preparation of2-{[(2-(4-Hydroxyphenoxy)ethyl)thio]methyl}-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole

To a solution of2-{[(2-(4-benzoyloxyphenoxy)ethyl)thio]methyl-5-{4-[(4-(N,N-dimethylamino)butanoyl)amino]phenyl}-1,3,4-oxadiazole(50 mg, 0.1 mmol) in MeOH (1 mL) and tetrahydrofuran (0.5 mL) was added2M NaOH (1 mL, 2 mmol). The mixture was stirred at room temperatureovernight and extracted with methylene chloride (3×5 mL). The combinedmethylene chloride extracts were washed with water (1 mL), dried(MgSO₄), and concentrated to give a colorless oil (30 mg, 66%).

¹H NMR (CDCl₃) δ 10.60 (s, 1H), 7.86 (d, 2H, J=8.4 Hz), 7.58 (d, 2H,J=8.4 Hz), 6.72 (d, 2H, J=8.8 Hz), 6.67 (d, 1H, J=9.2 Hz), 4.07 (t, 2H,J=6.2 Hz), 4.0 (s, 2H), 3.01 (t, 2H, J=6.2 Hz), 2.44˜2.56 (m, 4H), 2.34(s, 6H), 1.83˜1.92 (m, 2H). IR (film, cm⁻¹) 3458, 3333, 2965, 1660,1597, 1500, 1410, 1395, 1264, 1163, 757. MS (ES+) m/e 457 (M+1). Anal.Calcd for C₂₃H₂₈N₄O₄S: C, 60.51; H, 6.18; N, 12.27; S, 7.02. Found C,61.02; H, 6.26; N, 12.09; S, 7.08.

Example 160 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-{3-hydroxymethyl-4-[((2-piperidinoethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazole

a) 5-{2-[((2-Phenoxyethyl)thio)methyl]-1,3,4-oxadiazol-5-yl}phthalide

To a mixture of 4-carboxyphthalide (178 mg, 1 mmol), 2-phenoxythioacetichydrazide hydrochloride (316 mg, 1.2 mmol),4-(N,N-dimethylamino)phenyldiphenylphosphine (917 mg, 3 mmol), andtriethylamine (607 mg, 6 mmol) in acetonitrile (10 mmol) was addedcarbon tetrachloride (770 mg, 5 mmol). The resultant mixture was stirredat room temperature overnight and concentrated. The residue waspartitioned between ether (50 mL) and 2 M HCl (30 mL). The organic layerwas washed with 2 M HCl (5×20 mL), dried (MgSO₄), and concentrated. Theresidue was triturated from methylene chloride and hexanes to give awhite solid (186 mg, 51%). The reaction was repeated on 3 mmol scale togive the same product (652 mg, 59%).

¹H NMR (CDCl₃) δ 8.16 (d, 1H, J=8.1 Hz), 8.13 (s, 1H), 8.02 (d, 1H,J=7.8 Hz), 7.22–7.26 (m, 2H), 6.93 (t, 1H, J=7.3 Hz), 6.86 (d, 2H, J=8.0Hz), 5.37 (s, 2H), 4.20 (t, 2H, J=5.8 Hz), 4.09 (s, 2H), 3.05 (t, 2H,J=5.9 Hz). MS (ES⁺) m/e 369 (M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-{3-hydroxymethyl-4-[((2-piperidinoethyl)amino)carbonyl]phenyl}-1,3,4-oxadiazolo

Lithium aluminum hydride (1 M in ether, 1 mL, 1 mmol) was diluted withtetrahydrofuran (1 mL) and N-(2-aminoethyl)piperidine (641 mg, 5 mmol)in tetrahydrofuran (1 mL) was added dropwise over 3 min. The resultantmixture was stirred at room temperature for 2 hr, diluted withtetrahydrofuran (4 mL), and5-{2-[((2-phenoxyethyl)thio)methyl]-1,3,4-oxadiazol-5-yl}phthalide (368mg, 1 mmol) was added. Stirring was continued at room temperatureovernight and tetrahydrofuran (5 mL), followed by 2 M NaOH (5 mL) wasadded. The mixture was stirred for 30 min, diluted with water (15 mL),and extracted with ethyl acetate (3×15 mL). The combined ethyl acetateextracts were washed with brine (15 mL), dried (MgSO₄), andconcentrated. The residue was recrystallized from methylene chloride andhexanes (1:1) to give a white solid (280 mg, 56%).

¹H NMR (CDCl₃) δ 8.02 (s, 1H), 8.0 (d, 1H, J=8.0 Hz), 7.64 (d, 1H, J=7.7Hz), 7.22–7.26 (m, 2H), 7.10 (br s, 1H), 6.92 (t, 1H, J=7.3 Hz), 6.87(d, 2H, J=8.4 Hz), 4.64 (s, 2H), 4.19 (t, 2H, J=6.0 Hz), 4.05 (s, 2H),3.59 (dd, 2H, J=8.2, 5.5 Hz), 3.04 (t, 2H, J=5.9 Hz), 2.60 (t, 2H, J=5.7Hz), 2.4˜2.52 (m, 4H), 1.60–1.66 (m, 4H), 1.47–1.50 (m, 21). IR (KBr,cm⁻¹) 3465, 3310, 2940, 2888, 2854, 1638, 1556, 1496, 1420, 1297, 1020,750. MS (ES+) m/e 497 (M+1). Anal. Calcd for C₂₆H₃₂N₄O₄S: C, 62.88; H,6.49; N, 11.28; S, 6.46. Found C, 63.27; Hp 6.46; N, 11.14; S, 6.28.

Example 161 Preparation of2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(2-benzyl-2-aminoacetamido)phenyl]-1,3,4-oxadiazole

a)2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-benzyl-2-((tert-butoxycarbonyl)amino)acetamido]phenyl}-1,3,4-oxadiazole

To a mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole (327mg, 1 mmol), Boc-L-phenylalanine (796 mg, 3 mmol), and1-hydroxybenzotriazole (405 mg, 3 mmol) in tetrahydrofuran (25 mL) wasadded diisopropylcarbodiimide (379 mg, 3 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate (25 mL), washed with 2 M NaOH (3×10 mL) and brine (25mL), dried (MgSO₄), and concentrated. The residue was purified bychromatography (silica gel) to give a yellow solid (167 mg, 29%).

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.4 Hz), 7.80 (d, 2H, J=8.4 Hz),7.22–7.32 (m, 7H), 6.93 (t, 1H, J=7.5 Hz), 6.87 (d, 2H, J=7.7 Hz), 5.08(br s, 1H), 4.18 (t, 2H, J=6.2 Hz), 4.02 (s, 2H), 3.78 (t, 1H, J=6.4Hz), 3.14 (d, 2H, J=6.9 Hz), 3.03 (t, 2H, J=6.2 Hz), 1.12 (s, 9H). MS(ES+) m/e 575 M+1).

b)2-{[(2-Phenoxyethyl)thio]methyl}-5-[4-(2-benzyl-2-aminoacetamido)phenyl]-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[2-benzyl-2-((tert-butoxycarbonyl)amino)acetamido]phenyl}-1,3,4-oxadiazole(144 mg, 0.25 mmol) and 25% trifluoroacetic acid in methylene chloride(2.5 mL) was stirred at room temperature overnight and concentrated. Theresidue was taken up in methylene chloride (15 mL), washed with 2 M NaOH(2×10 mL), dried (MgSO₄), and concentrated. The residue was purified bychromatography (silica gel, 10% methanol/methylene chloride) to give awhite solid (74 mg, 60%).

¹H NMR (CDCl₃) δ 9.69 (s, 1H), 7.98 (d, 2H, J=8.8 Hz), 7.74 (d, 2H,J=8.7 Hz), 7.23–7.34 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.89 (d, 2H, J=8.8Hz), 4.19 (t, 2H, J=6.2 Hz), 4.03 (s, 2H), 3.75 (dd, 1H, J=9.5, 4.0 Hz),3.37 (dd, 2H, J=13.9, 3.7 Hz), 3.04 (t, 2H, J=6.2 Hz), 2.80 (dd, 1H,J=13.9, 9.5 Hz). IR (KBr, cm⁻¹) 3430, 3060, 2981, 2926, 1681, 1599,1501, 1426, 1386, 1238, 1094, 744. MS (ES+) m/e 475 (M+1). Anal. Calcdfor C₂₆H₂₆N₄O₃S: C, 65.80; H, 5.52; N, 11.81; S, 6.76. Found C, 65.70;H, 5.56; N, 11.68; S, 6.61.

Example 162 Preparation of(S)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-benzyl-2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

A mixture of2-{[(2-phenoxyethyl)thio]methyl}-5-[4-(2-benzyl-2-aminoacetamido)phenyl]-1,3,4-oxadiazole(61 mg, 0.125 mmol), 2-(N,N-dimethylamino)ethylchloride hydrochloride(72 mg, 0.5 mmol), sodium carbonate (211 mg, 2 mmol), and sodium iodide(75 mg, 0.5 mmol) in ethanol (5 mL) was stirred under reflux overnight.The reaction mixture was poured into water (20 mL) and extracted withmethylene chloride (3×10 mL). The combined methylene cholride extractswere dried (MgSO₄) and concentrated. The residue was purified bychromatorgraphy (silica gel, 10% methanol/methylene chloride) to givethe desired product (30 mg, 44%) and recovered starting amine (13 mg,21%).

¹H NMR (CDCl₃) δ 10.06 (s, 1H), 7.98 (d, 2H, J=8.5 Hz), 7.78 (d, 2H,J=8.8 Hz), 7.23–7.33 (m, 7H), 6.93 (t, 1H, J=7.3 Hz), 6.88 (d, 2H, J=8.4Hz), 4.20 (t, 2H, J=6.0 Hz), 4.03 (s, 2H), 3.32–3.42 (m, 2H), 3.04 (t,2H, J=6.2 Hz), 2.74 (dd, 1H, J=13.9, 10.2 Hz), 2.54–2.58 (m, 2H), 2.38(m, 1H), 2.24 (m, 1H), 2.09 (s, 6H). MS (ES+) m/e 546 (M+1). Anal. Calcdfor C₃₀H₃₅N₅O₃S: C, 66.03; H, 6.46; N, 12.83; S, 5.88. Found C, 66.18;H, 6.37; N, 12.71; S, 6.01.

Example 163 Preparation of(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-methyl-2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

a) (+)-Ethyl 2-[(2-nitrobenzenesulfonyl)amino]propionate

A solution of 2-nitrobenzenesulfonyl chloride (6.0 g, 27.1 mmol) andDL-alanine ethyl ester hydrochloride (5.0 g, 32.5 mmol) in methylenechloride (250 mL) was cooled in an ice/water bath. Triethylamine (9.5mL, 67.8 mmol) was added dropwise over 3 min. The reaction was stirredfor 10 min in the ice/water bath, then at room temperature for 3 h. Themixture was extracted with 2N HCl (3×100 mL), dried (MgSO₄), filteredand concentrated to yield 8.1 g (98%) of a yellow solid.

¹H NMR (CDCl₃) δ 8.05 (m, 1H), 7.89 (m, 1H), 7.69 (m, 2H), 6.07 (d, 1H,J=8 Hz), 4.19 (m, 1H), 3.93 (dd, 2H, J=14 and 14 Hz), 1.45 (dd, 3H, J=3and 6 Hz), 1.07 (dt, 3H, J=14 and 14 Hz). MS (ES+) m/e 303 (M+1).

b) (+)-Ethyl2-[N-(2-nitrobenzenesulfonyl)-N-(N′,N′-dimethylamino)-1,2-ethanediamino]propionate

A solution of ethyl (+)-ethyl2-[(2-nitrobenzenesulfonyl)amino]propionate (3.0 g, 10 mmol),N,N-dimethylethanolamine (2.0 mL, 20 mmol) and triphenylphosphine (6.56g, 25 mmol) in THF (100 mL) were cooled in an ice/water bath. Diethylazodicarboxylate (4.0 mL, 25 mmol) was added dropwise over 3 min,stirred another 10 min, then stirred at room temperature for 16 h. Themixture was concentrated, diluted with methanol (20 mL) and loaded ontoa column containing Bio-Rad 50W-X2 cation exchange resin (50 g,pre-washed 800 mL of methanol). The column was washed with methanol (800mL) and methylene chloride (200 mL). The product was then eluted with 2Nammonia/methanol (500 mL) and concentrated to yield 3.34 g of a yellowoil. This material was diluted with ethyl acetate (50 mL), extractedwith water (3×50 mL), dried (MgSO₄), filtered and concentrated to yield2.92 g (78%) of a yellow oil.

¹H NMR (CDCl₃) δ 8.07 (m, 1H), 7.65 (m, 2H), 7.57 (m, 1H), 4.75 (m, 1H),4.03 (m, 2H, 3.56 (m, 1H), 3.17 (m, 1H), 2.63 (m, 1H), 2.46 (m, 1H),2.20 (s, 6H), 1.51 (d, 3H, J=7 Hz), 1.12 (t, 3H, J=14 Hz). MS (ES+) m/e375 (M+1).

c)(+)-2-[N-(2-Nitrobenzenesulfonyl)-N—(N′,N′-dimethylamino)-1,2-ethanediamino]propionicacid

A solution of (+)-ethyl2-[N-(2-nitrobenzenesulfonyl)-N-(N′,N′-dimethylamino)-1,2-ethanediamino]propionate(2.92 g, 7.8 mmol) and aqueous 2 N NaOH (20 mL, 40 mmol) intetrahydrofuran (14 mL) was stirred at room temperature for 2 h. Themixture was loaded onto a column of Bio-Rad AG1-X2 anionic exchangeresin (40 g, pre-washed with 800 mL of water) and allowed to settle for20 min before it was passed through the column. The column was washedwith water (800 mL) and 1,4-dioxane (600 mL). The product was theneluted with 4 N HCl in 1,4-dioxane and concentrated to yield 2.06 g(76%) of a yellow oil.

¹H NMR (DMSO-D6) δ 10.00 (br s, 1H), 8.17 (m, 1H), 7.80–7.92 (m, 3H),4.55 (m, 1H), 4.15 (m, 1H), 3.80 (m, 1H), 3.75 (m, 2H), 2.75 (s, 6H),1.45 (d, 2H, J=7 Hz). MS (ES−) m/e 344 (M−1).

d)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[(2-(N′,N′-dimethyl-N-(2-nitrobenzenesulfonyl)-1,2-ethanediamino)propionyl)amino]phenyl}-1,3,4-oxadiazole

A solution of(+)-2-[N-(2-nitrobenzenesulfonyl)-N-(N′,N′-dimethylamino)-1,2-ethanediamino]propionicacid (345 mg, 1 mmol) and2-{[(2-phenoxyethyl)thio]methyl}-5-(4-aminophenyl)-1,3,4-oxadiazole (327mg, 1 mmol) in anhydrous pyridine (3.0 mL) was cooled in an ice-saltwater bath under nitrogen. Phosphorus oxychloride (0.15 mL, 1.6 mmol)was added dropwise and the cooled reaction stirred for 3 h. The reactionwas quenched with water (10 mL) and extracted with ethyl acetate (3×10mL). The combined organic phase was extracted with saturated aqueoussodium bicarbonate (3×10 mL), water (3×10 mL) and brine (3×10 mL), dried(MgSO₄), filtered and concentrated. The residue was co-evaporated withtoluene (3×5 mL) to remove any lingering pyridine. This material waspurified by preparative TLC (5% methanol/methylene chloride) to yield147 mg (22%) of a brown oil.

¹H NMR (CDCl₃) δ 8.59 (br s, 1H), 8.16 (d, 1H, J=9 Hz), 7.97 (d, 2H, J=9Hz), 7.63–7.75 (m, 5H), 7.25 (m, 2H), 6.93 (m, 1H), 6.87 (d, 2H, J=8Hz), 4.18 (m, 3H), 4.02 (s, 2H), 3.91 (m, 1H), 3.42 (m, 1H), 3.02 (m,2H), 2.55 (m, 1H), 2.43 (m, 1H), 2.24 (s, 6H), 1.40 (t, 3H, J=14 Hz). MS(ES+) m/e 655 (M+1).

e)(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-methyl-2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

A mixture of(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[(2-(N′,N′-dimethyl-N-(2-nitrobenzenesulfonyl)-1,2-ethanediamino)propionyl)amino]phenyl}-1,3,4-oxadiazole(147 mg, 0.22 mmol), benzenethiol (0.04 mL, 0.39 mmol) and potassiumcarbonate (93 mg, 0.67 mmol) was stirred in N,N-dimethylformamide (2.0mL) at room temperature for 1 h. The mixture was diluted with ethylacetate (40 mL), extracted with water (5×10 mL), dried (MgSO₄), filteredand concentrated to yield 182 mg of a brown oil. This residue waspurified by preparative TLC (10% methanol/methylene chloride) to yield35 mg (33%) of a colorless oil.

¹H NMR (CDCl₃) δ 9.97 (s, 1H), 7.97 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8Hz), 7.26 (m, 2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.88 (d, 2H, J=8 Hz),4.19 (t, 2H, J=12 Hz), 4.02 (s, 2H), 3.26 (m, 1H), 3.04 (t, 2H, J=12Hz), 2.81 (m, 1H), 2.64 (m, 1H), 2.47 (m, 1H), 2.37 (m, 1H), 2.24 (s,6H), 1.40 (d, 2H, J=7). IR (film, cm⁻¹) 3421, 3071, 2977, 2938, 1683,1603, 1499, 1413, 1242, 732. MS (ES+) m/e 470 (M+1). Anal. Calcd forC₂₄H₃₁N₅O₃S: C, 61.38; H, 6.65; N, 14.91; S, 6.83. Found C, 61.86; H,6.62; N, 15.06; S, 6.41.

Example 164 Preparation of(+)-2-{[(2-Phenoxyethyl)thio]methyl}-5-{4-[2-isobutyl-2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazole

This compound was prepared similarly to(+)-2-{[(2-phenoxyethyl)thio]methyl}-5-{4-[2-methyl-2-(N′,N′-dimethylethylenediamino)acetamido]phenyl}-1,3,4-oxadiazolefrom DL-alanine ethyl ester hydrochloride.

¹H NMR (CDCl₃) □ 9.98 (s, 1H), 7.96 (d, 2H, J=9 Hz), 7.76 (d, 2H, J=9Hz), 7.25 (m, 2H), 6.93 (dd, 1H, J=7 and 8 Hz), 6.87 (d, 2H, J=8 Hz),4.19 (t, 2H, J=12 Hz), 4.02 (s, 2H), 3.18 (m, 1H), 3.04 (t, 2H, J=12Hz), 2.76 (m, 1H), 2.65 (m, 1), 2.47 (m, 1H), 2.39 (m, 1H), 2.24 (s,6H), 1.65–1.78 (m, 2H), 1.48 (m, 1H), 0.96 (dd, 6H, J=2 and 9 Hz). IR(film, cm⁻¹) 2958, 2867, 2250, 1684, 1601, 1505, 1240, 909, 734, 650. MS(ES+) m/e 512 (M+1). Anal. Calcd for C₂₇H₃₇N₅O₃S: C, 63.38; H, 7.29; N,13.69; S, 6.27. Found C, 63.70; H, 6.73; N, 13.79; S, 5.93.

Example 165 Preparation ofN-(3-Dimethylamino-propyl)-4-[5-(3-phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) (3-Phenoxy-propoxy)-acetic acid tert-butyl ester

To a solution of 3-phenoxypropanol (5 g, 32.8 mmol) in 30 mL toluene wasadded tert-butylbromoacetate (19.2 g, 99 mmol) and tetrabutylammoniumhydrogen sulfate (2.8 g, 8.2 mmol). The mixture was cooled to 0° C. andtreated with 25 mL 50% aqueous NaOH. After stirring for 10 minutes at 0°C. the cooling bath was removed and the reaction was stirred at ambienttemperature for 2 hours. It was diluted with 50 mL toluene and thelayers were separated. The aqueous layer was extracted with 50 mLtoluene and the combined organic layer was dried over MgSO₄ beforeconcentrating to dryness. The resulting colorless oil was purified bychromatography using EtOAc in hexanes to recover 6.1 g (23 mmol, 69%) ofthe desired product as an oil. MS (ES) m/e 378

¹H NMR (CDCl₃) δ 7.29–7.25 (m, 2H), 6.95–6.89 (m, 3H), 4.11–4.07 (m,2H), 3.97 (s, 2H), 3.72–3.69 (m, 2H), 2.11–2.08 (m, 2H) and 1.47 (s,9H).

b) (3-Phenoxy-propoxy)-acetic acid

(3-Phenoxy-propoxy)-acetic acid tert-butyl ester (7.6 g, 29 mmol) wasmixed with 18 g anisole and 50 mL CH₂Cl₂ then treated with 25 mL TFA.The mixture was stirred at ambient temp overnight, concentrated todryness under vacuum and purified by chromatography using MeOH in CHCl₃to recover 5.5 (26 mmol, 90%) of the desired product as an oil. MS (ES)m/e 211

¹H NMR (CDCl₃) δ 10.55 (bs, 1H), 7.3–7.6 (m, 21), 6.97–6.90 (m, 3H),4.15 (s, 2H), 4.14–4.10 (m, 2H), 3.78–3.75 (m, 2H), 2.14–2.08 (m, 2H).

c) 4-Hydrazinocarbonyl-benzoic acid methyl ester

A mixture of dimethyl terephthalate (11 g, 57 mmol) and 350 mL MeOH wastreated with 2 mL (62 mmol) of anhydrous hydrazine. The mixture wasrefluxed for 4 hours, cooled to room temp and filtered. The filtrate wasallowed to stand at room temp for several hours then refiltered. Thesecond filtrate was concentrated to dryness, mixed with 200 mL THF,refluxed for several minutes then allowed to stand at room temperaturefor several hours. The solid was filtered to recover 3.9 g (20 mmol,35%) product as white crystals. MS (ES) m/e 211

¹H NMR (DMSO-d6) δ 9.95 (s, 1H), 8.0–7.98 (m, 2H), 7.92–7.90 (m, 2H),4.56 (s, 2H), and 3.30 (s, 3H).

d) 4-{N′-[2-(3-Phenoxy-propoxy)-acetyl]-hydrazino}-benzoic acid methylester

A mixture of (3-phenoxy-propoxy)-acetic acid (3 g, 14.3 mmol) in 25 mLCH₂Cl₂ was treated with an excess (1 mL) oxalyl chloride and 1 drop ofDMF then stirred overnight. After concentration to dryness under vacuum,the residue was dissolved in 10 mL CH₂Cl₂ and added to a cold (0° C.)mixture of 125 mL pyridine and the 4-hydrazinocarbonyl-benzoic acidmethyl ester. The reaction was stirred overnight at ambient temperature,concentrated to dryness under vacuum and purified by chromatographyusing EtOAc in hexanes to recover 2.7 g of oil which crystallized.

¹H NMR (CDCl₃) δ 9.36–9.35 (m, 1H), 9.11–9.09 (m, 1H), 8.07–8.03 (m,2H), 7.82–7.80 (m, 2H), 7.28–7.22 (m, 2H), 6.94–6.86 (m, 3H), 4.12–4.06(m, 4H), 3.94 (s, 3H), 3.79–3.76 (m, 2H), and 2.15–2.07 (m, 2H).

e) 4-[5-(3-Phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester

A mixture of 4 {N′-[2-(3-Phenoxy-propoxy)-acetyl]-hydrazino}-benzoicacid methyl ester (2.3 g, 6 mmol) and 25 mL SOCl₂ was refluxed overnightand concentrated to dryness under vacuum. Residual SOCl₂ was remover bymixing with toluene and reconcentrating to an oil. After dissolving in16 mL CH₂Cl₂ and 4 mL MeOH, it was treated with 3 mL 2 Mtrimethylsilyldiazomethane in hexanes, reconcentrated to dryness andpurified by silica gel chromatography using EtOAc in hexanes to recover0.8 g of product.

¹H NMR (CDCl₃) δ 8.15–8.08 (m, 4H), 7.24–7.21 (m, 2H), 6.91–6.84 (m,3H), 4.79 (s, 2H), 4.08–4.06 (m, 2H), 3.96 (s, 3H), 3.82–3.79 (m, 2H),2.13–2.07 (m, 2H).

f) 4-[5-(3-Phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid

4-[5-(3-Phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acidmethyl ester (0.8 g, 2.3 mmol) was dissolved in 50 mL THF, treated with3.5 mL 1 M aqueous LiOH, and stirred overnight at ambient temperature.The reaction was neutralized with 3.5 mL 1 N HCl, mixed with 20 mL brineand extracted twice with 20 mL EtOAc. The extracts were dried over MgSO4and concentrated to 550 mg (1.6 mmol, 68%) of a white solid which wasused as isolated in the next procedure.

¹H NMR (DMSO-d6) δ 8.15–8.08 (m, 4H), 7.24–7.21 (m, 2H), 6.91–6.84 (m,3H), 4.08–4.06 (m, 2H), 3–96 (s, 3H), 3.82–3.79 (m, 2H), 2.13–2.07 (m,2H).

g)N-(3-Dimethylamino-propyl)-4-[5-(3-phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzamide

4-[5-(3-Phenoxy-propoxymethyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid (500mg, 1.4 mmol) was converted to it's acid chloride by mixing with 50 mLCH₂Cl₂, 2 mL oxalyl chloride and 2 drops of DMF and stirring for 1 hour.After concentration to dryness it was re-dissolved in 10 mL CH₂Cl₂ andadded to a cold mixture of 3-dimethylaminopropylamine (317 mg, 3.1 mmol)in 30 mL CH₂Cl₂. The reaction was stirred at 0° C. for 1 hour,concentrated to dryness then purified by silica gel chromatography usingMeOH in CHCl₃ to recover 250 mg white solid.

¹H NMR (CDCl₃) δ 8.81. (s, 1H), 8.10–8.07 (m, 2H), 7.88–7.86 (m, 2H),7.25–7.22 (m, 2H), 6.92–6.85 (m, 3H), 4.78 (s, 2H), 4.09–4.06 (m, 2H),3.82–3.79 (m, 2H), 3.62–3.58 (m, 2H), 2.55–2.52 (m, 2H), 2.3 (s, 6H),2.13–2.07 (m, 21, 1.81–1.75 (m, 2H).

Anal. Calcd for C₂₄H₃₀N₄O₄.0.2C₄H₁₀O.0.1H₂O: C, 65.19; H, 7.15; N,12.26. Found C, 65.33; H, 6.86; N, 12.60.

Example 166 Preparation ofN-(3-Dimethylamino-propyl)-4-{5-[(4-phenoxy-butyrylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-benzamide

a)4-{N′-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetyl]-hydrazinocarbonyl}-benzoicacid methyl ester

Starting from 4-hydrazinocarbonyl-benzoic acid methyl ester andN-phthaloylglycine, this compound was prepared in 69% yield in a similarmanner as exemplified in example 165 d.

¹H NMR (DMSO-d6) δ 10.66 (s, 1H), 10.45 (s, 1H), 8.05–8.03 (m, 2H),7.96–7.91 (m, 4H), 7.88–7.85 (m, 2H), 4.34 (s, 2H), 3.86 (s, 3H) MS (ES)m/e 382.

b)4-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester

4-{N′-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetyl]-hydrazinocarbonyl}-benzoicacid methyl ester (5 g, 13.11 mmol) was mixed with 100 mL SOCl₂ andrefluxed over night. Concentration under vacuum gave a solid which wastritrated with MeOH to recover 3 g (8.3 mmol, 63%) of the product as awhite solid.

¹H NMR (DMSO-d6) δ 8.14–8.07 (m, 4H), 7.96–7.94 (m, 2H), 7.93–7.87 (m,2H), 5.15 (s, 211, 3.87 (s, 3H).

c)4-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

A mixture of4-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester (6 g, 16.5 mmol), thiophenol (3.6 g, 33 mmol),Potassium fluoride (1.9 g, 33 mmol) and N-methylpyrrolidinone (60 mL)was heated in a sealed tube at 180° C. for 60 hours. The reaction waspoured into 200 mL brine, diluted with 40 mL 5N HCl and extracted 3times with 200 mL EtOAc. The combined extracts was dried over MgSO₄ andconcentrated to dryness under vacuum. The residue was mixed with 50 mLCHCl₃ and filtered to recover 3.5 g solid.

¹H NMR (DMSO-d6) δ 12.0 (t, 1H), 8.1–8.0 (m, 2H), 7.95–7.85 (m, 21),7.8–7.7 (m, 1H), 7.6–7.5 (m, 1H), 7.4–7.3 (m, 21), 7.7–7.8 (m, 2H). MS(ES) m/e 350.

d)4-(5-Aminomethyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylamino-propyl)-benzamide

A mixture of4-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-benzoicacid (4 g, 11.45 mmol), 3-dimethylaminopropyl amine (1.4 g, 13.7 mmol)and triethylamine (2.3 g, 22.9 mmol) in 100 mL dry DMF was cooled to 0°C. and treated with dicyclohexylcarbodiimide (2.8 g, 13.7 mmol) andhydroxy benzotriazole (1.86 g, 13.7 mmol). The cooling bath was removedand the reaction was stirred for 2 hours before adding an additional 1 g(4.8 mmol) of dicyclohexylcarbodiimide. After stirring an additional 18hours it was concentrated to dryness under vacuum, mixed with 250 mLCHCl3 and filtered. The filtrate was purified by 2 chromatographies onsilica using CHCl3 and MeOH then THF, Hexanes and triethylamine to give2 g of a solid. This was further purified using an ion exchange columnto recover 1.7 g of an oil.

The above oil was dissolved in 50 mL EtOH and treated with 1 mLhydrazine monohydrate. After refluxing for 15 minutes, the reaction wasconcentrated to dryness, mixed with 30 mL MeOH and filtered. Thefiltrate was purified by ion exchange chromatography to recover 1.2 g ofa solid.

¹H NMR (CDCl₃) δ 8.75–8.65 (m, 1H), 8.10–8.0 (m, 41), 3.95 (s, 2H),3.3–3.25 (m, 4H), 2.3–2.25 (m, 2H), 2.15 (s, 6H), 1.7–1.6 (m, 2H).

Anal. Calcd for C₁₅H₂₁N₅O₂: C, 59.39; H, 6.98; N, 23.01. Found C, 59.11;H, 7.04; N, 22.78. MS (ES) m/e 304

e)N-(3-Dimethylamino-propyl)-4-{5-[(4-phenoxy-butyrylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-benzamide

A mixture of the4-(5-aminomethyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylamino-propyl)-benzamide(150 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (147 mg, 0.74 mmol), 3-phenoxybutyric acid (133 mg, 0.74mmol) and triethylamine (200 mg, 2 mmol) in 20 mL dry DMF was stirredfor 4 hours. Concentrated to an oil under vacuum, mixed with CHCl₃ andpurified by chromatography on silica using a mixture of CHCl₃, MeOH andammonium hydroxide to recover 78 mg (0.17 mmol, 33%) of a white solid.MS (ES) m/e 304

¹H NMR (CDCl₃) δ 8.92 (s, 1H), 8.03–8.01 (m, 2H), 7.84–7.82 (m, 2H),7.27–7.23 (m, 2H), 6.94–6.86 (m, 3H), 6.63–6.60 (m, 1H), 4.77–4.75 (m,2H), 4.05–4.02 (m, 2H) 3.60–3.56 (m, 2H), 2.56–2.51 (m, 4H), 2.30 (s,6H), 2.22–2.15 (m, 2H), 1.8–1.74 (m, 2H). Anal. Calcd for C₂₅H₃₁N₅O₄: C,64.50; H, 6.73; N, 15.22. Found C, 64.50; H, 6.71; N, 15.04.

Example 167 Preparation ofN-(3-Dimethylamino-propyl)-4-{5-[(3-phenoxy-propionylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-benzamide

Starting from 3-phenoxy propionic acid and4-(5-aminomethyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylamino-propyl)-benzamidethis compound was prepared in 13% yield using the procedure exemplifiedin Example 166 e.

MS (ES) m/e 452

¹H NMR (CDCl₃) δ 8.92 (s, 1H), 8.03–8.01 (m, 2H), 7.84–7.82 (m, 2H),7.29–7.25 (m, 2H), 6.98–6.90 (m, 4H), 4.81–4.79 (m, 2H), 4.32–4.30 (m,2H), 3.59–3.48 (m, 2H), 2.82–2.79 (m, 2H), 2.54–2.51 (m 211), 2.31 (s,6H), 1.80–1.74 (m, 2H). Anal. Calcd for C₂₄H₃₀N₄O₄.0.2C₄H₁₀.0.5H₂O: C,62.59; H, 6.57; N, 15.21. Found C, 62.93; H, 6.27; N, 15.23.

Example 168 Preparation ofN-(3-Dimethylamino-propyl)-4-{5-[(5-phenoxy-pentanoylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-benzamide

Starting from 3-phenoxybutyric acid and4-(5-aminomethyl-[1,3,4]oxadiazol-2-yl)-N-(3-dimethylamino-propyl)-benzamidethis compound was prepared in 22% yield using the procedure procedureexemplified in Example 166 e.

MS (ES) m/e 480. ¹H NMR (CDCl₃) δ 8.92 (s, 1H), 8.04–8.02 (m, 2H),7.84–7.82 (m, 2H), 7.28–7.23 (m, 2H), 6.94–6.85 (m, 3H), 6.57 (s, 1H),4.76–4.75 (m, 2H), 4.00–3.97 (m, 2H), 3.60–3.56 (m, 2), 2.54–2.51 (m,2H), 2.43–2.40 (m 2), 2.30 (s, 6H), 1.92–1.84 (m, 4H), 1.80–1.74 (m,2H). Anal. Calcd for C₂₆H₃₃N₅O₄.0.2H₂O: C, 64.63; H, 6.96; N, 14.50.Found C, 64.37; H, 6.76; N, 14.41.

Example 169 Preparation ofDimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenoxy}-propyl)-amineHydrochloride

a) 4-(4-Chloromethyl-oxazol-2-yl)-phenol

A solution of 4-hydroxy-benzamide (3.20 g, 23.33 mmol) and 1,3-dichloroacetone (5.93 g, 46.66 mmol) in 40 mL dimethylformamide was warmed to120° C. for 4 h. The reaction mixture was allowed to cool to roomtemperature and poured into 50 g of ice/water. The resulting precipitatewas filtered and dried in vacuo to afford 3.98 g (82%)2-(4-hydroxyphenyl)-4-chloromethyl-oxazole as a white solid.

¹H NMR (DMSO-D₆, 300 MHz): δ 10.12 (s, 1H), 8.15 (s, 1H), 7.81 (d, 2H,J=9 Hz), 6.89 (d, 2H, J=9 Hz), 4.70 (s, 2H). MS (MH⁺) 210.

b) 4-[4-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol

A solution of sodium hydride (200 mg, 8.34 mmol) in ethanol (47 mL) wastreated with 2-phenoxy-ethanethiol (1.17 g, 7.59 mmol) in 5 mL ethanolat room temperature and stirred for 10 minutes.4-(4-Chloromethyl-oxazol-2-yl)-phenol (1.99 g, 9.48 mmol) was added andstirring was continued for 16 hours. The solvent was evaporated in vacuoand the remains were poured into 50 mL water. The precipitate wasfiltered and dried in vacuo. The solid was stirred in 8 mL solventmixture of hexane and tert.-butyl methylether (10:1), and dried again invacuo to afford 2.13 g (86%)4-[4-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol as a whitesolid.

¹H NMR (DMSO-D₆, 300 MHz): δ 10.18 (br s, 1H), 7.95 (s, 1H), 7.78 (d,2H, J=9 Hz), 7.27 (d, 2H, J=12 Hz), 6.96–6.85 (m, 5H), 4.17 (t, 2H, J=7Hz), 3.76 (s, 2H), 2.92 (t, 2H, J=7 Hz). MS (MH⁺)328.

c)Dimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenoxy}-propyl)-amineHydrochloride

A suspension of 4-[4-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol(524 mg, 1.60 mmol), dimethyl 3-chloro-propyl-amine hydrochloride (304mg, 1.92 mmol), and potassium carbonate (531 mg, 3.84 mmol) indimethylformamide (20 mL) was heated at 80° C. for 14 hours. The solventwas removed in vacuo and the remains partitioned between water andmethylene chloride. The organic layer was dried over sodium sulfate andevaporated. The remaining oil was purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol containing 10%ammonia) to afford a white solid. The solid was dissolved in 10 mLdioxane and treated with 0.1 mL 4M HCl in dioxane and stirred for 10minutes. Ether was added and the precipitation filtered and dried invacuo to afford 204 mg (28%) ofdimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenoxy}-propyl)-amineas a white solid.

¹H NMR (DMSO-D₆, 300 MHz): δ 10.42 (br s, 1H), 8.01 (s, 1H), 7.90 (d,2H, J=9 Hz), 7.28 (t, 2H, J=8 Hz), 7.09 (d, 2H, J=9 Hz), 6.99–6.88 (m,3H), 4.22–4.10 (m, 4H), 3.78 (s, 2H), 3.26–3.17 (m, 2H), 2.93 (t, 2H,J=7 Hz), 2.79 (s, 3H), 2.78 (s, 3H), 2.23–2.12 (m, 2H). MS (MH⁺) 413.

Example 170 Preparation ofDimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenoxy}-propyl)-amine

a) 4-(4-Methoxy-phenyl)-2-vinyl-oxazole

A solution of ω-bromo acetophenone (11.93 g, 52.08 mmol), 2,6di-tert.-butyl-4-methyl-phenol as a stabilizer (1.15 g, 5.21 mmol), andacryl amide (7.40 g, 104.16 mmol) were dissolved in 360 mLdimethylformamide and heated at 150° C. for 4 hours. The solvent wasevaporated and the remaining oil dissolved in 200 mL ethyl acetate andwashed with 150 mL water. The organic layer was dried over sodiumsulfate and evaporated and the remaining oil purified by chromatographyon silica gel (elution with gradient hexane/ethyl acetate) to afford5.59 g (53%) of 4-(4-methoxy-phenyl)-2-vinyl-oxazole as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ 7.76 (s, 1H), 7.67 (d, 2H, J=9 Hz), 6.94 (d,2H, J=9 Hz), 6.65 (dd, 1H, J=18 Hz, J=11 Hz), 6.22 (d, 1H, J=18 Hz),5.65 (d, 1H, J=11 Hz), 3.34 (s, 3H). MS (MH⁺)202.

b) 4-(4-Methoxy-phenyl)-oxazole-2-carbaldehyde

A solution of 4-(4-methoxy-phenyl)-2-vinyl-oxazole (3.06 g, 15.21 mmol),N-methyl-morpholine N-oxide (2.16 g, 15.97 mmol),hydrochinidine-(1,4-phthalazindiyl-diether) (116 mg, 1.49 mmol) in 70 mLacetone: water (4:1) was treated with 4 mL of 0.079 M aqueous osmiumtetroxide solution and was stirred at room temperature for 4 hours. Thesolvent was evaporated in vacuo and remaining oil was dissolved in 150mL methylene chloride and washed with 50 mL 10% aqueous sodium sulfitesolution. The organic layer was dried over sodium sulfate andevaporated. The remaining oil was dissolved in 50 mL tert.-butylmethylether and 50 mL water and treated with sodium meta periodate andstirred for 4 hours. The organic layer was than separated, dried oversodium sulfate and evaporated to afford 1.5 g (49%) of4-(4-methoxy-phenyl)-oxazole-2-carbaldehyde as a colourless oil.

¹H NMR (CDCl₃, 300 MHz): δ 9.82 (s, 1H), 8.04 (s, 1H), 7.73 (d, 2H, J=9Hz), 6.98 (d, 2H, J=9 Hz), 3.87 (s, 3H). MS (MH⁺) 204.

c) [4-(4-Methoxy-phenyl)-oxazol-2-yl]-methanol

A solution of 4-(4-methoxy-phenyl)-oxazole-2-carbaldehyde (1.27 g, 6.23mmol) in 50 mL ethanol: water (4:1) was treated with sodium borohydride(236 mg, 6.23 mmol) and stirred at room temperature for 30 minutes. Thereaction was quenched with 2 mL acetone and evaporated. The remainingoil was dissolved in 75 mL methylene chloride and washed with 50 mLwater. The organic layer was dried over sodium sulfate and evaporatedand the remaining oil purified by chromatography on silica gel (elutionwith gradient hexane/ethyl acetate) to afford 1.17 g (92%)[4-(4-methoxy-phenyl)-oxazol-2-yl]-methanol as white crystals.

¹H NMR (CDCl₃, 300 MHz): δ 7.78 (s, 1H), 7.63 (d, 2H, J=9 Hz), 6.93 (d,2H, J=9 Hz), 4.77 (s, 2H), 3.83 (s, 3H). MS (MH⁺) 206.

d) 2-Chloromethyl-4-(4-methoxy-phenyl)-oxazole

A solution of [4-(4-methoxy-phenyl)-oxazol-2-yl]-methanol (861 mg, 4.2mmol) in 10 mL carbon tetrachloride was treated with triphenylphosphine(1.18 g, 4.49 mmol) and heated at 80° C. for 7 hours. The solvent wasevaporated and the remaining yellow solid purified by chromatography onsilica gel (elution with gradient methylene chloride/ethanol) to afford769 mg (82%) 2-chloromethyl-4-(4-methoxy-phenyl)-oxazole as yellowcrystals.

¹H NMR (CDCl₃, 300 MHz): δ 7.83 (s, 1H), 7.65 (d, 2H, J=9 Hz), 6.94 (d,2H, J=9 Hz), 4.65 (s, 2H), 3.85 (s, 3H). MS (MH⁺)224.

e) 4-(2-Chloromethyl-oxazol-4-yl)-phenol

2-Chloromethyl-4-(4-methoxy-phenyl)-oxazole (753 mg, 3.37 mmol) wasdissolved in 20 mL methylene chloride, cooled to −70° C. and treatedwith 6.74 ml 1M boron tribromide solution in methylene chloride. Within2 hours the reaction mixture was allowed to warm to room temperature andquenched with 15 mL saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with 10 mL 2M hydrochloric acid, dried oversodium sulfate and evaporated to afford 682 mg (97%)4-(2-chloromethyl-oxazol-4-yl)-phenol as a white solid.

¹H NMR (CDCl₃) δ 7.83 (s, 1H), 7.59 (d, 2H, J=9 Hz), 6.87 (d, 2H, J=9Hz), 5.42 (br S, 1H), 4.65 (s, 2H). MS (MH⁺) 210.

f) 4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenol

A solution of sodium hydride (82 mg, 3.42 mmol) in 3 mL ethanol wastreated with 2-phenoxy-ethanethiol (502 mg, 3.25 mmol) in 2 mL ethanolat room temperature and stirred for 10 minutes.4-(2-Chloromethyl-oxazol-4-yl)-phenol (682 mg, 3.25 mmol) was added andstirring was continued for 72 hours. The solvent was evaporated in vacuoand the remains were poured into 50 mL water. The precipitate wasfiltered, dried in vacuo to afford 1.02 g (96%)4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenol as a whitesolid.

¹H NMR (CDCl₃, 300 MHz): δ 7.77 (s, 1H), 7.75 (d, 2H, J=9 Hz), 7.26 (t,2H, J=7 Hz), 6.98–6.82 (m, 5H), 4.16 (t, 2H, J=6 Hz), 3.93 (s, 2H), 3.03(t, 2H, J=6 Hz). MS (MH⁺) 328.

g)Dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenoxy}-propyl)-amine

A suspension of 4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenol(1.00 g, 3.05 mmol), dimethyl 3-chloro-propyl-amine hydrochloride (507mg, 3.21 mmol), and potassium carbonate (929 mg, 6.72 mmol) indimethylformamide (20 mL) was heated at 80° C. for 24 hours. The solventwas removed in vacuo and the remains partitioned between water andmethylene chloride. The organic layer was dried over sodium sulfate andevaporated. The remaining oil was purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol containing 10%ammonia) to afford 765 mg (61%) ofdimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-4-yl]-phenoxy}-propyl)-amineas white solid.

¹H NMR (CDCl₃, 300 MHz): δ 7.77 (s, 1H), 7.62 (d, 2H, J=9 Hz), 7.26 (t,2H, J=7 Hz), 6.97–6.86 (m, 5H), 4.17 (t, 2H, J=7 Hz), 4.04 (t, 2H, J=7Hz), 3.93 (s, 2H), 3.04 (t, 2H, J=7 Hz), 2.46 (t, 2H, J=7 Hz), 2.27 (s,6H), 2.02–1.92 (m, 2H). MS (MH⁺) 413.

Example 171 Preparation ofDimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-10phenoxy}-propyl)-amine Hydrochloride

a) 4-Chloromethyl-2-(4-methoxy-phenyl)-thiazole

A solution of 4-methoxy-thiobenzamide (1.90 g, 11.33 mmol) and1,3-dichloro acetone (2.8 g, 22.6 mmol) in 20 mL dimethylformamide waswarmed to 100° C. for 2 h. The reaction mixture was allowed to cool toroom temperature and poured into 30 g of ice/water. The resultingprecipitate was filtered and dried in vacuo to afford 1.60 g (59%)4-chloromethyl-2-(4-methoxy-phenyl)-thiazole as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ 7.88 (d, 2H, J=9 Hz), 7.23 (s, 1H), 6.95 (d,2H, J=9 Hz), 4.72 (s, 2H), 3.83 (s, 3H). MS (MH⁺) 240.

b) 4-(4-Chloromethyl-thiazol-2-yl)-phenol

4-Chloromethyl-2-(4-methoxy-phenyl)-thiazole (1.0 g, 4.17 mmol) wasdissolved in 20 mL methylene chloride, cooled to −70° C. and treatedwith 8.34 ml 1M boron tribromide solution in methylene chloride. Within2 hours the reaction mixture was allowed to warm to room temperature andquenched with 15 mL saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with 10 mL 2M hydrochloric acid, dried oversodium sulfate and evaporated. The solid was stirred with 5 mL methylenechloride. The remaining solid was dried in vacuo to afford 795 mg (85%)4-(4-chloromethyl-thiazol-2-yl)-phenol as a white solid.

¹H NMR (DMSO-D₆, 300 MHz): δ 9.80 (br s, 1H), 7.77 (d, 2H, J=9Hz), 7.67(s, 1H), 6.87 (d, 2H, J=9 Hz), 4.83 (s, 2H). MS (MH⁺) 226.

c) 4-[4-(2-Phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenol

A solution of sodium hydride (80 mg, 3.34 mmol) in 5 mL ethanol wastreated with 2-phenoxy-ethanethiol (490 mg, 3.18 mmol) in 2 mL ethanolat room temperature and stirred for 10 minutes.4-(4-chloromethyl-thiazol-2-yl)-phenol (790 mg, 3.18 mmol) was added andstirring was continued for 16 hours. The solvent was evaporated in vacuoand the remains were poured into 50 mL water and extracted with ethylacetate. The organic layer was dried over sodium sulfate and evaporated.The remaining oil was purified by chromatography on silica gel (elutionwith gradient methylene chloride/ethanol containing 10% ammonia) toafford 767 mg (70%)4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenol as a whitesolid.

¹H NMR (CDCl₃, 300 MHz):

7.80 (d, 2H, J=8 Hz), 7.26 (t, 2H, J=9, Hz), 7.07 (s, 1H), 6.98–6.80 (m,5H), 5.69 (s, 1H), 4.18 (t, 2H, J=7 Hz), 3.99 (s, 2H), 2.96 (t, 2H, J=7Hz).

MS (MH⁺) 344.

d)Dimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenoxy}-propyl)-amineHydrochloride

A suspension of4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenol (751 mg, 2.19mmol), dimethyl 3-chloro-propyl-amine hydrochloride (363 mg, 2.30 mmol),and potassium carbonate (665 mg, 4.81 mmol) in dimethylformamide (15 mL)was heated at 80° C. for 14 hours. The solvent was removed in vacuo andthe remains partitioned between water and methylene chloride. Theorganic layer was dried over sodium sulfate and evaporated. Theremaining oil was purified by chromatography on silica gel (elution withgradient methylene chloride/ethanol containing 10% ammonia) to afford awhite solid. The solid was dissolved in 10 mL dioxane and treated with0.5 mL 4M HCl in dioxane and stirred for 10 minutes. Ether was added andthe precipitation filtered and dried in vacuo to afford 546 mg (54%) ofdimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiazol-2-yl]-phenoxy}-propyl)-amineas a white solid.

¹H NMR (DMSO-D₆, 300 MHz): δ 10.49 (br s, 1H), 7.86 (d, 2H, J=9 Hz),7.46 (s, 1H), 7.27 (t, 2H, J=8 Hz), 7.04 (d, 2H, J=9 Hz), 6.97–6.89 (m,3H), 4.22–3.98 (m, 6H), 3.97 (s, 2H), 3.26–3.17 (m, 2H), 2.94 (t, 2H,J=7 Hz), 2.79 (s, 3H), 2.77 (s, 3H), 2.23–2.11 (m, 2H). MS (MH⁺) 429.

Example 172Dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-amine

a) 2-Chloro-N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-acetamide

6.30 g (31 mmol) ω-amino-4-methoxy acetophenon hydrochloride wassuspended in 70 mL methylene chloride and treated with 8.6 mL (62 mmol)triethylamine. 2.46 ml (31 mmol) of chloro acetylchloride was added dropwise under slight cooling (˜10° C.). After complete addition thereaction mixture was stirred at room temperature for 24 h. The reactionwas quenched with water (100 mL) and the organic layer was dried oversodium sulfate and evaporated to yield 7.45 g (100%)2-chloro-N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-acetamide.

¹H NMR (CDCl₃, 300 MHz): δ 7.96 (d, 2H, J=7 Hz), 7.68 (br s, 1H), 6.98(d, 2H, J=7 Hz), 4.73 (d, 2H, J=4 Hz), 4.13 (s, 2H), 3.89 (s, 3H).

b) 2-Chloromethyl-5-(4-methoxy-phenyl)-oxazole

1.7 g (7 mmol) of2-chloro-N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-acetamide was treated with20 ml of phosphorous oxychloride and stirred for 2 h at 100° C. The darkmixture was poured into water cautiously in portions. The temperaturewas held below 40° C. by addition of ice. After being basification withconc. aequous ammonia the mixture was extracted with tert.-butylmethylether. The organic layer was dried over sodium sulfate andevaporated to yield 1.5 g (96%) of2-chloromethyl-5-(4-methoxy-phenyl)-oxazole.

¹H NMR (CDCl₃, 300 MHz): δ 7.58 (d, 2H, J=9 Hz), 7.19 (s, 1H), 6.95 (d,2H, J=9 Hz), 4.66 (s, 2H), 3.85 (s, 3H).

c) 4-(2-Chloromethyl-oxazol-5-yl)-phenol

1.4 g (6.2 mmol) of 2-chloromethyl-5-(4-methoxy-phenyl)-oxazole weredissolved in 25 mL methylene chloride, cooled to −70° C., and treateddropwise with 12.4 mL of a borone tribromide solution (1M in methylenechloride). After complete addition the reaction mixture was allowed towarm to room temperature. The mixture was poured into ice/water,basified with saturated aequous sodium carbonate and acidified withaqueous 2M HCl solution. After extraction with methylene chloride,drying over sodium sulfate and evaporation, the crude product wasdissolved in 5 mL chloroform filtered and dried to yield 0.79 g (61%)4-(2-chloromethyl-oxazol-5-yl)-phenol.

¹H NMR (DMSO-d₆, 300 MHz): δ 9.86 (br s, 1H), 7.54 (d, 2H, J=9 Hz), 7.47(s, 1H), 6.86 (d, 2H, J=9 Hz), 4.91 (s, 2H).

d) 4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol

0.54 g (3.5 mmol) of 2-phenoxy-ethanethiol was dissolved in 8 ml ofethanol and treated with 1.75 mL (3.5 mmol) of 2M ethanolic sodiumethoxide solution. After stirring at room temperature for 10 minutes0.78 g (3.7 mmol) of 4-(2-chloromethyl-oxazol-5-yl)-phenol was added.Stirring at room temperature was continued for 20 hours. The solvent wasevaporated and the residue was treated with 100 mL water and 100 mLethyl acetate. The organic layer was dried over sodium sulfate andevaporated. The remaining oil was purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol) to afford 0.4 g(35%) 4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol.

¹H NMR (DMSO-d₆, 300 MHz): δ 9.78 (s, 1H), 7.48 (d, 2H, J=8 Hz), 7.36(s, 1H), 7.27 (t, 3H, J=8 Hz), 6.97–6.90 (m, 3H), 6.83 (d, 2H, J=8 Hz),4.16 (t, 2H, J=6 Hz), 4.02 (s, 2H), 2.99 (t, 2H, J=6 Hz). MS (MH⁺) 328.

e)Dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-amine

0.39 g (1.2 mmol) of4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 0.28 g (1.8mmol) of 3-dimethylaminopropyl chloride hydrochloride, and 0.5 g (3.6mmol) of potassium carbonate were dissolved in 10 mL dimethylformamideand heated to 80° C. for 65 hours. The reaction mixture was poured into100 mL water and was extracted with tertiarybutyl methylether. Theorganic layer was dried over sodium sulfate and evaporated. Theremaining oil was purified by HPLC to afford 70 mg (14%)dimethyl-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-amine.

¹H NMR (CDCl₃, 300 MHz): δ 7.53 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.85 (m, 5H), 4.17 (t, 2H, J=7 Hz), 4.05 (t, 2H, J=7 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=7 Hz), 2.47 (t, 2H, J=7 Hz), 2.27 (s, 6H),2.03–1.92 (m, 2H). MS (MH⁺) 413.

Example 1732-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 172 e, from 300 mg (0.92 mmol)4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 164 mg (0.962mmol) N-(2-chloro-ethyl)-pyrrolidine hydrochloride, and 278 mg (2.015mmol) potassium carbonate in 6 mL DMF.

Yield: 209 mg (53%).

¹H NMR (CDCl₃, 300 MHz): δ 7.53 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.87 (m, 5H), 4.17 (t, 2H, J=7 Hz), 4.14 (t, 2H, J=7 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=7 Hz), 2.96–2.88 (m, 2H), 2.68–2.61 (m,4H), 1.86–1.78 (m, 4H). MS (MH⁺) 425.

Example 174Dimethyl-(2-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazo-5-yl]-phenoxy}-ethyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 172e, from 455 mg (1.39 mmol) of4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 210 mg (1.46mmol) (2-chloro-ethyl)-dimethyl-amine hydrochloride, and 423 mg (3.06mmol) of potassium carbonate in 9 mL DMF. Yield: 304 mg (55%).

¹H NMR (CDCl₃, 300 MHz): δ 7.53 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.87 (m, 5H), 4.17 (t, 2H, J=6 Hz), 4.10 (t, 2H, J=6 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=6 Hz), 2.75 (t, 2H, J=6 Hz), 2.35 (s, 6H).MS (MH⁺) 399.

Example 1751-(2-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-ethyl)-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 172e, from 455 mg (1.39 mmol)4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 269 mg (1.46mmol), N-(2-chloro-ethyl)-piperidine hydrochloride, and 423 mg (3.06mmol) of potassium carbonate in 9 mL DMF. Yield: 414 mg (68%).

¹H NMR (CDCl₃, 300 MHz): δ 7.53 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.87 (m, 5H), 4.17 (t, 2H, J=7 Hz), 4.14 (t, 2H, J=7 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=6 Hz), 2.79 (t, 2H, J=6 Hz), 2.56–2.48 (m,4H), 1.67–1.57 (m, 4H), 1.50–1.41 (m, 2H). MS (MH⁺) 439.

Example 1761-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 172e, from 455 mg (1.39 mmol)4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 289 mg (1.46mmol) N-(3-chloro-propyl)-piperidine hydrochloride, and 423 mg (3.06mmol) potassium carbonate in 9 mL DMF. Yield: 525 mg (83%).

¹H NMR (CDCl₃, 300 MHz): δ 7.52 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.87 (m, 5H), 4.17 (t, 2H, J=6 Hz), 4.04 (t, 2H, J=6 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=6 Hz), 2.52–2.37 (m, 6H), 2.05–1.93 (m,2H), 1.66–1.55 (m, 4H), 1.50–1.40 (m, 2H). MS (MH⁺) 453.

Example 1772-(2-Phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-oxazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 172 e, from 455 mg (1.39 mmol)4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol, 269 mg (1.46mmol) N-(3-chloro-propyl)-pyrrolidine hydrochloride, and 423 mg (3.06mmol) potassium carbonate in 9 mL DMF. Yield: 470 mg (77%).

¹H NMR (CDCl₃, 300 MHz): δ 7.53 (d, 2H, J=9 Hz), 7.30–7.22 (m, 2H), 7.12(s, 1H), 6.98–6.87 (m, 5H), 4.17 (t, 2H, J=6 Hz), 4.14 (t, 2H, J=6 Hz),3.94 (s, 2H), 3.04 (t, 2H, J=7 Hz), 2.78 (t, 2H, J=7 Hz), 2.56–2.49 (m,4H), 1.67–1.58 (m, 4H), 1.50–1.41 (m, 2H). MS (MH⁺) 439.

Example 178 Preparation of2-(2-hydroxyethylthio)methyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazolehydrochloride from methyl 4-hydroxy-benzoate

a) Methyl 4-[3-(dimethylamino)propoxy]-benzoate

To a solution of 4-hydroxy benzoic acid methyl ester (50.0 g, 328.6mmol), triphenyl phosphine (130.0 g, 493.5 mmol), and3-dimethylamino-1-propanol (50.5 g, 57 ml, 493.5 mmol) in 1000 mL of dryTHF was added dropwise isopropyl azo dicarboxylate at 0° C. Aftercompleted addition the temperature was brought to ambient temperatureand the mixture was stirred for 16 h. The mixture was evaporated. It wasthen dissolved in ethyl acetate and extracted with 2N aqueous HCl. Theaqueous phase was made alkaline with solid sodium hydroxide pellets andextracted with ethyl acetate (3 times). The collected organic phaseswere dried with sodium sulphate and evaporated. The crude material (75g, 96%) was used directly in the next step.

¹H NMR (DMSO-d₆) δ 7.95 (d, 2H, J=8 Hz), 7.00 (d, 2H, J=8 Hz), 4.13 (t,2H, J=6 Hz), 3.83 (s, 3H), 2.32 (t, 2H, J=6 Hz), 2.13 (s 6H), and 1.88(quint., 2H, J=6 Hz), MS (FD) m/e 238.

b) 4-[3-(dimethylamino)propoxy]-benzoic acid hydrazide

A solution of methyl 4-[3-(dimethylamino)propoxy]-benzoate (108.0 g,457.0 mmol), in 443 ml (458 g, 9.14 M) of neat hydrazine hydrate wassubdivided into ten aliquots and each aliquot was heated in a Teflonbomb in a microwave oven ETHOS 1600 for 1 h to 120° C. After TLCindicated complete conversion the reaction mixture was poured in waterand extracted with DCM. The collected organic phases were dried oversodium sulphate, filtered and evaporated. The residue was purified viacolumn chromatography using a DCM/DCM-MeOH/DCM-MeOH-ammonia gradient(100% to 90:10). Yield 32.7 g (42%)

¹H NMR (DMSO-d₆) δ 9.58 (s, 1H, exch.), 7.80 (d, 2H, J=8 Hz), 6.98 (d,2H, J=8 Hz), 4.40 (s, 2H, br., exch.), 4.05 (t, 2H, J=6 Hz), 2.35 (t,2H, J=6 Hz), 2.15 (s 6H), and 1.88 (quint., 2H, J=6 Hz),. MS (FD) m/e238.

c) 4-[3-(dimethylamino)propoxy]-benzoic acid 2-(chloroacetyl)hydrazidehydrochloride

Chloro acetylchloride (2.40 g, 1.68 ml, 21.07 mmol) was slowly added toa solution of 4-[3-(dimethylamino)propoxy]-benzoic acid hydrazide (5.0g, 21.07 mmol) in 50 ml DCM. After stirring overnight at ambienttemperature TLC showed incomplete conversion. After successive additionof chloro acetyl chloride (0.17 ml, additional stirring for 2 h, 0.5 mladditional stirring for 1 h) TLC showed almost complete conversion. Themixture was diluted with 50 ml MTBE and the colorless precipitate thusformed was filtered off and dried in a vacuum oven at 40° C. for 1 h.6.7 g (91%) of colorless crystals. The material was used in the nextstep without purification.

d)2-Chloromethyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazolehydrochloride

4-[3-(dimethylamino)propoxy]-benzoic acid 2-(chloroacetyl)hydrazide (6.7g, 19.13 mmol) was added to 34 ml of phosphoryl chloride POCl₃ and themixture was stirred at 95° C. overnight. The mixture was diluted withDCM and evaporated to dryness. The residue was repeatedly trituratedwith toluene and evaporated to remove remaining traces of POCl₃ and HCl.The colorless residue was sufficiently pure for the next step.

¹H NMR (DMSO-d₆) δ 10.58 (s, 1H, exch.), 7.98 (d, 2H, J=8 Hz), 7.20 (d,2H, J=8 Hz), 5.12 (s, 2H), 4.18 (t, 2H, J=6 Hz), 3.20 (t, 2H, J=6 Hz),2.80 (d 6H, J=4 Hz), and 2.20 (quint., 2H, J=6 Hz),. MS (FD) m/e 296.1.

e)2-(2-hydroxyethylthio)methyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazolehydrochloride

To a solution of sodium ethylate in ethanol, prepared by adding sodiumhydride (60% dispersion, 2.1 g, 51.96 mmol) to 90 ml of absolute ethanolwas added 2-mercaptoethanol (4.1 g, 51.96 mmol, 3.7 ml). The mixture wasstirred at room temperature for 30 min. Then2-chloromethyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazolehydrochloride (8.6 g, 25.98 mmol) was added as a solid. After 2 hstirring at ambient temperature the mixture was evaporated. The residuewas suspended in DCM (dichloromethane) and extracted with aqueous sodiumbicarbonate. The organic phase was dried over sodium sulphate andevaporated the residue was purified via flash chromatography on silicagel using DCM-DCM/ethanolic ammonia gradient (100% to 90% DCM) yielding4.8 g (49%) of pure compound.

¹H NMR (DMSO-d₆) δ 7.90 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 4.88 (t,1H, exch.), 4.10 (m, 2H), 4.10 (s, 2H), 3.57 (q, 2H), 2.72 (t, 2H, J=4Hz), 2.36 (t, 2H, J=4 Hz), 2.18 (s, 6H) and 1.88 (quint. 2H, J=4 Hz). MS(FD) m/e 338.1.

f)Dimethyl-(3-{4-[5-(2-(4-fluorophenoxy-ethylsulfanylmethyl)-1,3,4-oxadiazol-2-yl]-phenoxy}-propyl)-amine

To a mixture of2-(2-hydroxyethylthio)methyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazolehydrochloride (0.200 g, 0.592 mmol), 4-fluorophenol (0.100 mg, 0.888mmol) triphenyl phosphine polystyrene resin (0.888 g, 0.888 mmol, 1meq./g) in 6 ml DCM was added diisopropyl azodicarboxylate (0.180 g, 176μl, 0.888 mmol) and stirred at ambient temperature for 12 h. The mixturewas evaporated and redissolved in methanol. The solution was purifiedvia a SCX-cartidge using 20 ml methanol to remove impurities. Thecompound was eluted with methanolic ammonia. The residue (206 mg) wasfinally purified via prep. HPLC (RP-18) using acetonitrile/water/0.1%TFA gradient yielding 44 mg (17%) of the desired compound

¹H NMR (DMSO-d₆) δ 9.50 (s, br, exch) 7.89 (m, 2H), 7.05 (m, 6H), 4.25(s, 2H), 4.10 (m, 2H), 3.90 (m, br 2H), 3.23 (m, 2H), 3.05 (q, 2H), 2.80(2 s, 6H), and 2.12 (m, 2H). MS (FD) m/e 432.1.

The following compounds were prepared using the protocol describedabove, using2-(2-hydroxyethylthio)methyl-5-(4-[3-(dimethylamino)propoxy]-phenyl)-1,3,4-oxadiazoleand the appropriate substituted phenol. After prep. HPLC the appropriatefractions were collected, evaporated and redissolved in methanol.Filtration of the methanolic solution of the trifluoroacetate salts ofthe desired compounds through SCX cartridges yielded the free bases ofthe desired compounds:

Example 179

¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8 Hz), 7.00 (m, 4H), 6.98 (d, 2H, J=8Hz), 6.65 (m, 3H), 4.28 (t, 2H), 4.11 (s, 2H), 4.10 (t, 2H), 3.10 (t,2H), 2.40 (t, 2H), 2.30 (s, 6H), and 2.00 (quint., 2H). MS (FD) m/e432.1.

Example 180

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.20 (m, 1H), 6.98 (d, 2H, J=8Hz), 6.65 (m, 3H), 4.20 (t, 2H), 4.12 (t, 2H), 4.03 (s, 2H), 3.05 (t,2H), 2.45 (t, 2H), 2.25 (s, 6H), and 2.00 (quint., 2H). MS (FD) m/e432.1.

Example 181

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 7.00 (d,2H, J=8 Hz), 6.85 (m, 2H), 4.25 (t, 2H), 4.13 (t, 2H), 4.08 (s, 2H),3.10 (t, 2H), 2.50 (t, 2H), 2.28 (s, 6H), 2.23 (s, 3H), and 1.98(quint., 2H). MS (FD) m/e 428.1.

Example 182

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.15 (t, 1H, J=8 Hz), 7.00 (d,2H, J=8 Hz), 6.75 (m, 2H), 4.20 (t, 2H), 4.10 (t, 2H), 4.05 (s, 2H),3.05 (t, 2H), 2.45 (t, 2H), 2.33 (s, 3H), 2.30 (s, 6H), and 1.98(quint., 2H). MS (FD) m/e 428.1.

Example 183

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8 Hz), 7.08 (d, 1H, J=8 Hz), 7.20 (t,1H), 7.00 (d, 2H, J=8 Hz), 6.80 (d, 2H, J=8 Hz), 4.18 (t, 2H), 4.10 (t,2H), 4.05 (s, 2H), 3.07 (t, 2H), 2.50 (t, 2H), 2.27 (s, 6H), 2.26 (s,3H), and 2.00 (quint., 21). MS (FD) m/e 428.2.

Example 184

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8 Hz), 7.33 (d, 1H, J=8 Hz), 7.20 (t,1H), 7.00 (d, 2H, J=8 Hz), 6.90 (d, 2H, J=8 Hz), 6.70 (d, 1H), 4.30 (t,2H), 4.15 (s, 2H), 4.10 (t, 2H), 3.10 (t, 2H), 2.50 (t, 2H), 2.27 (s,6H), and 2.00 (quint., 2H). MS (FD) m/e 448.1.

Example 185

¹H NMR (CDCl₃) δ 7.88 (d, 2H, J=8 Hz), 7.11 (t, 1H, J=8 Hz), 6.90 (d,2H, J=8 Hz), 6.75 (m, 2H), 6.70 (d, 1H), 4.10 (t, 2H), 4.02 (t, 2H),3.98 (s, 2H), 3.01 (t, 2H), 2.40, (t, 2H), 2.21 (s, 6H), and 1.90(quint., 2H). MS (FD) m/e 448.0.

Example 186

¹H NMR (MeOD) δ 7.39 (d, 2H, J=8 Hz), 7.20 (d, 2.3 J=9 Hz), 7.02 (d, 2H,J=8 Hz), 6.83 (d, 2H, J=9 Hz), 4.20 (t, 21), 4.10 (t, 2H), 4.08 (s, 2H),3.07 (t, 2H), 2.55 (t, 2H), 2.35 (s, 6H), and 2.05 (quint., 2H). MS (FD)m/e 448.1.

Example 187

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8 Hz), 7.00 (d, 2H, J=8 Hz), 6.90 (m,4H), 4.20 (t, 2H), 4.10 (t, 2H), 4.05 (s, 2H) 3.78 (s, 3H), 3.07 (t,2H), 2.45 (t, 2H), 2.25 (s, 6H), and 1.98 (m, 2H). MS (FD) m/e 444.2.

Example 188

¹H NMR (CDCl₃) 7.95 (m, 2H), 7.15 (t, 1H, J=8 Hz), 7.00 (m, 2H), 6.42(m, 3H), 4.20 (t, 2H), 4.05 (t, 2H), 4.05 (s, 2H) 3.78 (s, 3H), 3.05 (t,2H), 2.45 (t, 2H), 2.25 (s, 6H), and 1.98 (m, 2H). MS (FD) m/e 444.2

Example 189

a) 4-[3-(dimethylamino)propoxy]-nitro benzene

To a suspension of 4-nitro phenol (30.0 g, 216 mmol), anhydrouspotassium carbonate (86.7 g, 627 mmol), and potassium iodide (5.5 g, 33mmol) in 360 ml of dry DMF was added finely ground3-dimethylamino-1-propyl chloride hydrochloride (51.7 g, 327 mmol). Themixture was stirred at 80° C. for 4 days. Successively another portionof 3-dimethylamino-1-propyl chloride hydrochloride (15.81 g, 100 mmol)and anhydrous potassium carbonate (25.2 g, 200 mmol) was added andstirring at 80° C. was continued for 16 h. After cooling the mixture wasdiluted with 1.5 l water and extracted with MTBE (2 times 600 ml). Thecollected organic phases were dried with sodium sulphate and evaporated.The crude yellow oil (31.7 g, 65.6%) was sufficiently pure and useddirectly in the next step.

¹H NMR (CDCl₃) δ 8.19 (d, 2H, J=8 Hz), 6.96 (d, 2H, J=8 Hz), 4.13 (t,2H, J=6 Hz), 2.48 (t, 2H, J=6 Hz), 2.28 (s 6H), and 2.00 (quint., 2H,J=6 Hz),.MS (FD) m/e 225.1.

b) 4-[3-(dimethylamino)propoxy]-aniline

To a solution of 4-[3-(dimethylamino)propoxy]-nitro benzene (12 g, 54mmol) in 65 ml of absolute ethanol was added 200 mg of Pd(OH)₂ on carbon(Pearlman's catalyst). The mixture was hydrogenated at atmospherichydrogen pressure for 16 h. The mixture was filtered over diatomeousearth and the filter cake rinsed with ethanol. The collected ethanolicfiltrates were evaporated. The crude orange oil (10.38 g, 99%) wassufficiently pure and used directly in the next step.

¹H NMR (CDCl₃) δ 6.83 (d, 2H, J=8 Hz), 6.72 (d, 2H, J=8 Hz), 3.83 (t,2H, J=6 Hz), 3.40 (s, br, exch. 2H) 2.42 (t, 2H, J=6 Hz), 2.25 (s 6H),and 1.91 (quint., 2H, J=6 Hz),.MS (ED) m/e 195.0.

c) 1-[4-(3-dimethylaminopropoxy)-phenyl)-1H-pyrrole-3-carboxaldehyde

To a solution of 3-formyl-(2,5-dimethoxytetrahydrofuran) (7.5 g, 47mmol) in 50 ml of glacial acetic acid was added4-[3-(dimethylamino)propoxy]-aniline (9.8 g, 50 mmol). A slightlyexothermic reaction occurred and the mixture darkened. The mixture wasstirred at 110° C. for 1 h and poured into 400 ml of crushed ice aftercooling to ambient temperature. The aqueous phase was neutralized withsolid sodium bicarbonate and exhaustively extracted with DCM.

The collected organic phases were dried over sodium sulphate andevaporated. The crude product was purified via flash chromatography onsilica gel using a DCM/DCM-ethanolic ammonia gradient 100 to 95:5. Areddish-brown oil was obtained (4.23 g, 33%).

¹H NMR (CDCl₃) δ 9.84 (s, 1H), 7.58 (t, 2H, J=2 Hz), 7.32 (d, 2H, J=8Hz), 7.00 (d, 2H, J=8 Hz), 7.00 (m, 1H), 6.77 (m, 1H), 4.08 (t, 2H, J=6Hz), 2.48 (t, 2H, J=6 Hz), 2.28 (s 6H), and 1.99 (quint., 2H, J=6Hz),.MS (FD) m/e 273.1.

d) 1-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrrole-3-methanol

To a stirred solution of DIBAH (17.1 ml, 20% in toluene, 21.2 mmol) wasadded 1-[4-(3-dimethylaminopropoxy)-phenyl)-1H-pyrrole-3-carboxaldehyde(2.9 g, 10.6 mmol) at 0 to 2° C. After stirring for 1 h at 0° C. thereaction was completed. Excess DIBAH was quenched with 10 ml oftoluene/methanol 1:1 under cooling. The gelatinous mixture wassolubilized with methanol and evaporated. The residue was extractedsuccessively with DCM and methanol and filtered off. The organicfiltrate was evaporated yielding a dark oil (3.0 g, 100%) whichsolidified in a freezer. According to HPLC the material was approx. 80%pure and was used without further purification.

¹H NMR (CDCl₃) δ 7.20 (d, 2H, J=8 Hz), 7.32 (d, 2H, J=8 Hz), 7.00 (d,2H, J=8 Hz), 6.90 (m, 4H), 4.55 (s, 2H), 3.95 (t, 2H, J=6 Hz), 2.40 (t,2H, J=6 Hz), 2.20 (s 6H), 1.90, (quint., 2H, J=6 Hz), and 1.70 (s, br,exch.1H). MS (FD) m/e 275.2.

2-Phenoxyethanethiol

The compound was prepared according to: J. Org. Chem. 1972, 37(10),1532–37.

To a stirred solution of1-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrrole-3-methanol (360 mg, 1.3mmol) in 15 ml of dry THF was added triethyl amine (334 mg, 3.3 mmol)and 10 mg DMAP and the mixture was cooled to −8° C. A solution ofmethane sulfonyl chloride (223 mg, 1.55 mmol) in 2 ml dry THF was addeddropwise and the mixture was stirred for 30 min at −5° C. TLC showedalmost complete conversion. After stirring for additional 2.5 h at −5 to0° C. the mixture was quenched with 60% sodium hydride (62 mg, 1.55mmol) and stirred for 15 min at 0° C. In the meantime a solution ofsodium 2-phenoxyethanethiolate was prepared from 2-phenoxy ethanethiol(401 mg, 2.6 mmol) and sodium hydride (60%, 104 mg, 2.6 mmol) in 2 mldry THF. After 15 min of stirring the solution was cooled to 0° C. andslowly added to the solution of the mesylate. The mixture was stirred at0° C. for 30 min and then for 16 h at ambient temperature. The mixturewas evaporated and the residue purified on an aluminum oxide (neutral)column. The main fraction was isolated as an orange oil (38 mg), whichwas 73% pure according to HPLC. The crude product was further purifiedby prep. HPLC (RP-18 acetonitrile/water/0.1% TFA) yielding 24.8 mg ofthe desired product as the triflate salt (3.6%).

¹H NMR (CDCl₃) δ 11.8 (s br. 1H), 7.26 (m, 4H), 6.92 (m, 7H,), 6.30 (t,1H, J=1 Hz), 4.10 (qu, qu, 4H), 3.88 (s, 2H), 3.30 (qu, 2H,), 2.90 (s+m,8H,), 2.28 (m, 2H). MS (FD) m/e 411.2.

2-Bromo-5-(chloromethyl)-thiophene

To a suspension of sodium borohydride (400 mg, 10.6 mmol) in 30 ml2-propanol was added dropwise a solution of5-bromothiophene-2-carboxaldehyde (2 g, 10.45 mmol) in 5 ml 2-propanolat ambient temperature. After stirring for 1 h at ambient temperaturethe mixture was carefully hydrolyzed by 2N aqueous hydrochloric acidunder ice cooling. The pH value was adjusted to 3 to 4 and the solutionwas extracted with DCM. The organic phase was dried over sodium sulfate,filtered and evaporated. The residue (1.9 g) was sufficiently pure forthe next step.

¹H NMR (CDCl₃) δ 6.91 (d, 1H, J=4 Hz), 6.75 (d, 1H, J=4 Hz), 4.75 (s,2H,), 1.90 (s, br., exch.).

A solution of the foregoing 2-bromo-5-thiophene methanol (1.9 g, 10.45mmol) and thionyl chloride (2.5 g) in 30 ml dry DCM was stirred atambient temperature for 2 h. The solution was evaporated and the residuerepeatedly re-dissolved in toluene and evaporated to remove traces ofthionyl chloride. The crude residue (2.1 g) was directly used in thenext step.

¹H NMR (CDCl₃) δ 6.92 (d, 1H, J=4 Hz), 6.83 (d, 1H, J=4 Hz), 4.70 (s,2H,). MS (FD) m/e 212.0.

2-Bromo-5-[(2-phenoxy)ethylthio)methyl]-thiophene

To a 2.5 N solution of sodium ethoxide (prepared from 120 mg, 5 mmol 60%sodium hydride and 20 ml of dry ethanol) was added dropwise2-phenoxyethanethiol (770 mg, 5 mmol) and stirred for 30 min at ambienttemperature. To this solution was added2-bromo-5-(chloromethyl)-thiophene (1000 mg, 5 mM dropwise and themixture was stirred over night at ambient temperature. The mixture wascarefully hydrolyzed with water and extracted with ethyl acetate. Theorganic phase was dried, filtered and evaporated. The residue waspurified via flash chromatography on silica gel using hexane/ethylacetate 97.5:2.5 yielding 1.2 g (79%) of the desired compound.

¹H NMR (CDCl₃) δ 7.30 (m, 2H), 6.92 (m, 4H), 6.71 (d, 2H, J=3 Hz), 4.41(t, 2H, J=6.5 Hz), 3.97 (s, 2H), 2.88 (t, 2H, J=6.5 Hz). MS (EI) m/e328.

a) 4-[3-(dimethylamino)propoxy]-iodo benzene

To a suspension of 4-iodo phenol (24.0 g, 110 mmol), anhydrous potassiumcarbonate (36.0 g, 260 mmol), and potassium iodide (2.2 g, 13 mmol) in240 ml of dry 2-butanone was added finely ground3-dimethylamino-1-propyl chloride hydrochloride (13.4 g, 110 mmol). Themixture was stirred under reflux for 48 h. The solvent was distilledoff. The residue was dissolved in DCM and extracted with 2N aqueous NaOHtwice. The organic phase was separated washed with water twice, driedand evaporated. The crude oil (21.0 g) was purified via flashchromatography on silica gel using a DCM/ethanolic ammonia gradient (100to 95:5) yielding 12.9 g of the desired compound sufficiently pure forthe next step.

¹H NMR (CDCl₃) δ 7.55 (d, 2H, J=8 Hz), 6.70 (d, 2H, J=8 Hz), 4.00 (t,2H, J=4 Hz), 2.45 (t, 2H, J=4 Hz), 2.23 (s 6H), and 1.95 (quint., 2H,J=4 Hz),.MS (FD) m/e 306.0.

[4-[3-(dimethylamino)propoxy]phenyl]boronic acid

To a solution of 4-[3-(dimethylamino)propoxy]-iodo benzene (1 g, 3.28mmol) in abs. THF was added a solution of n-butyl lithium in hexane (2.5ml, 1.6 M solution, 4 mmol) at −78° C. under vigorous stirring within 5min. After siring at −78° C. for 30 min a solution of trimethyl borate(433 μl, 3.94 mmol) in 10 ml abs. THF was added within 10 min andstirring at −78° C. continued for 2 h. Temperature was increased to −10°C. over 3 h and then to 0° C. The mixture was quenched with 1 ml ofwater and stirred for 80 h at room temperature. The precipitate thusformed was solubilized with 2 ml of methanol and the solution wasevaporated after adding 2.5 g silica gel. The coated silica gel wasloaded on an aluminum oxide column and eluted with a DCM/DCM-methanolgradient 100 to 90:10 yielding 200 mg (27%) of the desired compound.

¹H NMR (MeOD) δ 7.62 (d, 2H, br), 6.90 (d, 2H, J=8 Hz), 4.06 (t, 2H, J=4Hz), 2.63 (t, 2H, J=4 Hz), 2.38 (s 6H), and 1.98 (quint., 2H, J=4Hz),.MS (FD) m/e 224.1.

Example 190Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-thiophen-2-yl]-phenoxy}-propyl)-amine

To a solution of 2-bromo-5-[(2-phenoxy)ethylthio)methyl]-thiophene (247mg, 0,75 mmol) and [4-[3-(dimethylamino)propoxy]phenyl]boronic acid (200mg, 0.9 mM) in 40 ml of argon flushed dioxane was addedtetrakis(triphenylphosphine)palladium (0) (87 mg, 0.75 mmol) and 1,5 ml2 M aqueous sodium carbonate (3 mmol) under argon. The mixture washeated to 120° C. for 1 h in a microwave oven (MLS ETHOS 1600). TLCshowed complete conversion.

The reaction mixture was diluted with water and extracted with DCM. Theorganic phases were dried over sodium sulphate, filtered and evaporated.The residue was purified via flash chromatography on silica gel using aDCM/methanolic ammonia gradient 99:1–95:5 yielding the desired compoundalmost pure as the free base after two separations.

Final purification was achieved via HPLC on RP-18(acetonitrile/water/0.1% TFA gradient) yielding the trifluoro aceticacid salt as an oil.

The methanolic solution of the trifluoro acetate was poured on a SCXcolumn, which was rinsed with DCM/methanol and 7N methanolic ammonia toyield the free base. Yield 23%

Example 191 Alternative Synthesis ofdimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-thiophen-2-yl]-phenoxy}-propyl)-amine[4-[3-(dimethylamino)propoxy]phenyl]boronic acid pinacolyl ester (notisolated)

To a solution of 4-[3-(dimethylamino)propoxy]-iodo benzene (610 mg, 2.00mmol) in degassed 10 ml DMSO was added bis-(pinacolato)-diborane (558mg, 2.20 mmol), potassium acetate (200 mg, 6.0 mmol) and1.1-bis-(diphenylphosphino)-ferrocene-palladium(II)chloride DCM complex(200 mg, 0.24 mmol) under argon. The mixture was stirred by 90° C. for 3h. MS indicated complete conversion according to boron isotopedistribution. To this mixture was added a solution of2-bromo-5-[(2-phenoxy)ethylthio)methyl]-thiophene (790 mg, 2.4 mM) in 5ml degassed DMSO, PdCl₂dppf DCM complex (192 mg, 0.24 mmol) and 2 Maqueous sodium carbonate (2880 μl, 5.76 mmol) under argon. The mixturewas heated to 120° C. for 1 h in a microwave oven (MLS ETHOS 1600).After 1 hour mass spectrometry (MS) showed incomplete conversion.Addition of 0.24 mmol of Pd catalyst and prolonged heating for 1 h to120° C. in the microwave oven gave no major improvements. The reactionmixture was extracted with water, DCM and hexane. The organic layerswere dried over sodium sulphate, filtered and evaporated. The residuewas dissolved in methanol and poured on a 5 g SCX column, eluted withDCM/methanol and 7N methanolic ammonia and evaporated. The residue waspurified via flash chromatography on silica gel using a DCM/methanolicammonia gradient 99:1–97:3 yielding 250 mg (29%) of the desired compoundas free base.

The residue was dissolved in methanol/DCM and poured on a column with 2g Amberlite 748 (cation exchange resin) to remove Pd traces.

The filtrate was evaporated and purified via flash chromatography andprep HPLC on RP-18 (acetonitrile/water/0.1% TFA gradient) yielding 220mg (20%) of the desired compound as the trifluoroacetic acid salt as acolorless solid.

Trifluoracetate

¹H NMR (CDCl₃, 300 MHz)

11.66–11.32 (bs, 1H), 7.52–7.43 (d, 2H, J=9 Hz), 7.31–7.42 (m, 2H),7.02–6.99 (d, 1H, J=4 Hz), 6.99–6.92 (t, 1H, J=7 Hz), 6.92–6.82 (m, 5H),4.18–4.06 (t, 2H, J=7 Hz), 4.12–4.06 (t, 2H, 5 Hz), 4.05–4.01 (s, 2H),3.38–3.28 (m, 2H), 2.96–2.88 (m, 8H) and 2.33–2.22 (m, 2H). IR (CHCl₃,cm⁻¹) 1243, 1176, 1059 and 832. MS (ES) m/e 428.1.

Base

¹H NMR (CDCl₃, 300 MHz)

7.47 (d, 2H, J=9 Hz), 7.32–7.25 (m, 2H), 7.01–6.84 (m, 7H), 4.19–4.10(t, 2H, J=7 Hz 4.07–3.99 (m, 4H), 2.96–2.87 (t, 2H, J=7 Hz), 2.5–2.40(t, 2H, J=7 Hz), 2.29–2.21 (s, 6H) and 2.02–1.91 (m, 2H). IR (CHCl₃,cm⁻¹) 1246, 1176, 1032 and 832. MS (ES) m/e 428.1. Anal. Calcd forC₂₄H₂₉NO₂S₂: C, 67.41; H, 6.84; N, 3.28; S 15.00. Found C, 66.42; H,6.59; N, 3.34; S 14.30.

3-[4-(3-dimethylaminopropoxy)-phenyl)-thiophene-5-carboxaldehyde

[4-[3-(dimethylamino)propoxy]phenyl]boronic acid pinacolyl ester (notisolated)

To a solution of 4-[3-(dimethylamino)propoxy]-iodo benzene (1000 mg,3.28 mmol) in 20 ml DMSO was added bis-(pinacolato)-diborane (922 mg,3.63 mmol), potassium acetate (980 mg, 10.0 mmol) and1.1-bis-(diphenylphosphino)-ferrocene-palladium(II)chloride (82 mg, 0.10mmol). The mixture was stirred by 80° C. for 3 h. MS indicated completeconversion according to boron isotope distribution. This mixturecontaining the desired compound was directly used in the next step.

c)

To a solution of 4-bromo thiophene-2-carboxaldehyde (755 mg, 3.96 mmol)and 1.1-bis-(diphenylphosphino)-ferrocene-palladium(II)chloridedichloromethane complex (82 mg, 0.10 mmol) in 6.60 ml 2M aqueous sodiumcarbonate (1.32 mmol) was added the DMSO solution of the boronic acidderivative described above and the mixture was stirred for 16 h at 80°C. under argon. The mixture was cooled to room temperature and dilutedwith DCM. The solution was washed with water and brine, dried andevaporated. The residue was purified via flash chromatography on silicagel using a DCM-ethanolic triethyl amine gradient 99:1 to 90:10 yielding430 mg of the desired compound (45%).

¹H NMR (CDCl₃) □ 9.98 (s, 1H), 7.99 (d, 1H, J=1.5 Hz), 7.75 (d, 1H,J=1.5 Hz), 7.50 (d, 2H, J=8 Hz), 6.86 (d, 2H J=8 Hz), 4.05 (t, 2H, J=4Hz), 2.50 (t, 2H, J=4 Hz), 2.31 (s, 6H), and 2.00 (quint., 2H, J=4Hz),.MS (FD) m/e 290.1.

4-[4-(3-dimethylaminopropoxy)phenyl]-thiophene-2-methanol

To a solution of 20% DIBAH in toluene (2.97 ml, 3.6 mmol) was addeddropwise a solution of4-[4-(3-dimethylaminopropoxy)-phenyl)-thiophene-2-carboxaldehyde (430mg, 1.49 mmol) in 25 ml toluene at 0 to 2° C. The mixture was stirredfor 2 h at 0 to 2° C. and quenched with 5 ml methanol and evaporated.The solid residue was extracted with DCM and ethanol and the collectedorganic phases dried over sodium sulfate and evaporated. The residue waspurified via flash chromatography on silica gel using a DCM-ethanolicammonia gradient 99:1 to 90:10 yielding 280 mg (65%) of the desiredproduct.

¹H NMR (CDCl₃) □ 7.48 (d, 2H, J=8 Hz), 7.25 (m 2H), 6.96 (d, 2H J=8 Hz),4.80 (s, 2H), 4.03 (t, 2H, J=4 Hz), 2.45 (t, 2H, J=4 Hz), 2.28 (s, 6H),1.95 (quint., 2H, =4 Hz), and 1.70 (s, br., exch. 1H). MS (FD) m/e292.1.

Dimethyl-(3-{4-[4-(2-phenoxy-ethylsulfanylmethyl)-thiophen-2-yl]-phenoxy}-propyl)-amine

To a stirred suspension of4-[4-(3-dimethylaminopropoxy)phenyl]-2-thiophene-5-methanol (255 mg,0.87 mmol) in 10 ml of dry THF was added triethyl amine (223 mg, 2.20mmol) and 10 mg DMAP and the mixture was cooled to −8 to −10° C. Asolution of methane sulfonyl chloride (120 mg, 1.04 mmol) in 2 ml dryTHF was added dropwise and the mixture was stirred for 90 min at −5 to−10° C. TLC showed almost complete conversion. The mixture was quenchedwith 60% sodium hydride (42 mg, 1.04 mmol) and stirred for 15 min at 0°C. In the meantime a solution of sodium 2-phenoxyethanethiolate wasprepared from 2-phenoxy ethanethiol (269 mg, 1.74 mmol) and sodiumhydride (60%, 71 mg, 1.74 mmol) in 1.5 ml dry THF. After 15 min ofstirring the solution was cooled to 0° C. and slowly added to thesolution of the mesylate. The mixture was stirred at 0° C. for 30 minand then for 16 h at ambient temperature. The mixture was evaporated andthe residue purified by repeated chromatography on a silica gel column(DCM/ethanolic ammonia 99:1) yielding 180 mg of the desired product (48

¹H NMR (CDCl₃) δ 7.45 (d, 2H, J=8 Hz), 7.27 (m, 2H), 7.20 (m, 2H), 6.91(m, 5H,), 4.17 (t, 2H, J=4 Hz), 4.05 (t, 2H, J=4 Hz+s 2H), 2.95 (t, 2H,J=4 Hz), 2.52 (t, 2H, J=4 Hz), 2.28 (s, 6H), 1.98 (quint., 2H, J=4 Hz).MS (FD) m/e 428.2

a) 4-[3-(dimethylamino)propoxy]-iodo benzene

To a suspension of 4-iodo phenol (24.0 g, 110 mmol), anhydrous potassiumcarbonate (36.0 g, 260 mmol), and potassium iodide (2.2 g, 13 mmol) in240 ml of dry 2-butanone was added finely ground3-dimethylamino-1-propyl chloride hydrochloride (13.4 g, 110 mmol). Themixture was stirred under reflux for 48 h. The solvent was distilledoff. The residue was dissolved in DCM and extracted with 2N aqueous NaOHtwice. The organic phase was separated washed with water twice, driedand evaporated. The crude oil (21.0 g) was purified via flashchromatography on silica gel using a DCM/ethanolic ammonia gradient (100to 95:5) yielding 12.9 g of the desired compound sufficiently pure forthe next step.

¹H NMR (CDCl₃) δ 7.55 (d, 2H, J=8 Hz), 6.70 (d, 2H, J=8 Hz), 4.00 (t,2H, J=4 Hz), 2.45 (t, 2H, J=4 Hz), 2.23 (s 6H), and 1.95 (quint., 2H,J=4 Hz),.MS (FD) m/e 306.0.

b) 2-[4-(3-dimethylaminopropoxy)-phenyl)-furan-5-carboxaldehyde

b1) [4-[3-(dimethylamino)propoxy]phenyl]boronic acid pinacolyl ester(not isolated)

To a solution of 4-[3-(dimethylamino)propoxy]-iodo benzene (1000 mg,3.28 mmol) in 20 ml DMSO was added bis-(pinacolato)-diborane (922 mg,3.63 mmol), potassium acetate (980 mg, 10.0 mmol) and1.1-bis-(diphenylphosphino)-ferrocene-palladium(II)chloride (82 mg, 0.10mmol). The mixture was stirred by 80° C. for 3 h. MS indicated completeconversion according to boron isotope distribution. This mixturecontaining the desired compound was directly used in the next step.

c)

To a solution of 5-bromo furan-2-carboxaldehyde (690 mg, 3.935 mmol) and1.1-bis-(diphenylphosphino)-ferrocene-palladium(II)chloridedichloromethane complex (82 mg, 0.10 mmol)in 6.60 ml 2M aqueous sodiumcarbonate (1.32 mmol) was added the DMSO solution of the boronic acidderivative described above and the mixture was stirred for 16 h at 80°C. under argon. The mixture was cooled to room temperature and dilutedwith DCM. The solution was washed with water and brine, dried andevaporated. The residue was purified via flash chromatography on silicagel using a DCM-ethanolic triethyl amine gradient 99:1 to 90:10 yielding500 mg of the desired compound (56%).

¹H NMR (CDCl₃) □ 9.60 (s, 1H), 7.75 (d, 2H, J=6.5 Hz), 7.28 (d, 1H, J=4Hz), 6.97 (d, 2H J=6.5 Hz), 6.71 (d, 2H, J=4 Hz) 4.07 (t, 2H, J=4 Hz),2.50 (t, 2H, J=4 Hz), 2.30 (s, 6H,), and 2.00 (quint., 2H, J=4 Hz),.MS(FD) m/e 274.1.

5-[4-(3-dimethylaminopropoxy)phenyl]-furan-2-methanol

To a solution of 20% DIBAH in toluene (3.6 ml, 4.4 mmol) was addeddropwise a solution of5-[4-(3-dimethylaminopropoxy)-phenyl)-furan-2-carboxaldehyde (500 mg,1.83 mmol) in 25 ml toluene at 0 to 2° C. The mixture was stirred for 2h at 0 to 2° C. and quenched with 5 ml methanol and evaporated. Thesolid residue was extracted with DCM and ethanol and the collectedorganic phases dried over sodium sulfate and evaporated. The residue waspurified via flash chromatography on silica gel using a DCM-ethanolicammonia gradient 99:1 to 95:5 yielding 460 mg (91%) of the desiredproduct.

¹H NMR (CDCl₃) δ 7.60 (d, 2H, J=7 Hz), 6.90 (d, 2H J=7 Hz) 6.45 (d, 1H,J=3.5 Hz), 6.33 (d, 1H, J=3.5 Hz), 4.66 (s, 2H), 4.00 (t, 2H, J=4 Hz),2.43 (t, 2H, J=4 Hz), 2.21 (s, 6H), 1.92 (quint., 2H, J=4 Hz), and 1.80(s, br, exch 1H). MS (FD) m/e 276.2.

Example 192Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-furan-2-yl]-phenoxy}-propyl)-amine

To a stirred solution of5-[4-(3-dimethylaminopropoxy)phenyl]-2-furan-5-methanol (280 mg, 1.0mmol) in 16 ml of dry THF was added triethyl amine (258 mg, 2.55 mmol)and 10 mg DMAP and the mixture was cooled to −8 to −10° C. A solution ofmethane sulfonyl chloride (138 mg, 1.20 mmol) in 3 ml dry THF was addeddropwise and the mixture was stirred for 90 min at −5 to 0° C. TLCshowed almost complete conversion. The mixture was quenched with 60%sodium hydride (49 mg, 1.20 mmol) and stirred for 15 min at 0° C. In themeantime a solution of sodium 2-phenoxyethanethiolate was prepared from2-phenoxy ethanethiol (309 mg, 2.0 mmol) and sodium hydride (60%, 82 mg,2.0 mmol) in 2 ml dry THF. After 15 min of stirring the solution wascooled to 0° C. and slowly added to the solution of the mesylate. Themixture was stirred at 0° C. for 30 min and then for 16 h at ambienttemperature. The mixture was evaporated and the residue purified on asilica gel column. The crude product was further purified by prep. HPLC(RP-18 acetonitrile/water/0.1% TFA) yielding 230 mg of the desiredproduct as the triflate salt (56%).

¹H NMR (CDCl₃) δ 7.55 (d, 2H, J=8 Hz), 7.26 (m, 2H), 6.86 (m, 5H,), 6.42(d, 1H, J=2 Hz), 6.28 (d, 1H, J=2 Hz), 4.14 (t, 2H, J=4 Hz), 4.04 (t,2H, J=4 Hz), 3.88 (s, 2H), 2.96 (t, 2H, J=4 Hz), 2.45 (t, 2H, J=4 Hz),2.30 (s, 6H), 1.95 (quint., 2H, J=4 Hz). MS (FD) m/e 412.2.

Example 193 Preparation of(3-{4-[5-(1H-indol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

a) Thiobenzoic acidS-(2-{N′-[4-(3-dimethylamino-propoxy)benzoyl]hydrazino}-2-oxo-ethyl)ester

To a solution of benzoylsulfanyl-acetic acid (1.32 g, 6.7 mmol) in 45 mlTHF at room temperature was added 1,1′-carbonyldiimidazole. The solutionwas heated at 60° C. for eighty minutes then stirred at room temperaturefor forty minutes. Next, a solution of4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (1.59 g, 6.7 mmol)in 15 ml CH₃CN was added to the reaction. The solution was then stirredat room temperature for approximately 22 hours. The resultant suspensionwas filtered and the insoluble material was rinsed with CH₃CN to afford1.13 g (40%) of the title compound. The filtrate was concentrated to anoil then treated with water and extracted twice with EtOAc. The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated to asolid to afford an additional 2.08 g (74%) of the title compound and twoimpurities. The second lot containing the impurities was used insubsequent reactions.

¹H NMR (DMSO-d6)

10.28 (bs, 2H), 7.95 (d, 2H, J=7 Hz), 7.83 (d, 2H, J=9 Hz), 7.73 (m,1H), 7.59 (t, 2H, J=9 Hz), 7.00 (d, 2H, J=9 Hz), 4.06 (t, 2H, J=6 Hz),3.95 (s, 2H), 2.35 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.83–1.90 (m, 2H). IR(KBr, cm⁻¹) 3280, 2943, 2816, 2769, 1679, 1662, 1654, 1607, 1522, 1497,1295, 1253, 1211, 919 688. MS (ES⁺) m/e 416. MS (ES⁻) m/e 414.

b) Thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester

To a solution of Thiobenzoic acidS-(2-{N′-[4-(3-dimethylamino-propoxy)benzoyl]-hydrazino}-2-oxo-ethyl)ester (3.00 g, 7.2 mmol), triphenyl phosphine (3.79 g, 14.4 mmol) andtriethylamine (1.46 g, 14.4 mmol) at room temperature was added carbontetrachloride (2.22 g, 14.4 mmol). After stirring one hour at roomtemperature, carbon tetrabromide (2.39 g, 7.2 mmol) was added.Additional carbon tetrabromide (0.598 g, 1.8 mmol) was added fifteenminutes later. After stirring for approximately 3.5 hours, the resultantsuspension was filtered. The filtrate was concentrated to a semi-solidmaterial. Purification by normal phase chromatography (eluted with 9:1CH₃Cl:MeOH) afforded 2.65 g (92%) of thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester s anoil that slowly solidifies.

¹H NMR (DMSO-d6)

7.97 (m, 2H), 7.88 (m, 2H), 7.73 (m, 1H), 7.59 (t, 2H, J=8 Hz) 7.12 (m,2H), 4.69 (s, 2H), 4.08 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=7 Hz), 2.16 (s,6H), 1.87 (m, 2H). MS (ES⁺) m/e 398.

c)(3-{4-[5-(1H-indol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}-propyl)dimethylamine

A degassed solution of thiobenzoic acid S-{5-[4-(3-dimethylaminopropoxy)-phenyl]-[1,3,4]oxadiazol-2-yl}ester (0.264 g, 0.7 mmol) in 1.65ml MeOH and 0.85 ml H₂O was treated with lithium hydroxide (0.032 g, 1.3mmol). The reaction was stirred at room temperature for thirty minutesthen a mixture of 2-bromomethylindole-1-carboxylic acid methyl ester(0.178 g, 0.7 mmol) in 1 ml MeOH and 2 ml THF was added. After stirringat room temperature for three hours the mixture was concentrated toremove bulk of methanol. The mixture was diluted with EtOAc then washedtwice with water and once with brine. The organic layer was dried overNa₂SO₄, filtered and was concentrated to an oil. Purification by normalphase radial chromatography (eluted with 5% 2M NH3 in MeOH:CHCl₃)afforded a solid. Crystallization of the solid from Et2O:MeOH afforded0.066 g (17%) of(3-{4-[5-(1H-indol-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}-propyl)dimethylamine.

¹H NMR (DMSO-d6)

11.11 (bs, 1H), 7.84 (d, 2H, J=9 Hz), 7.44 (d, 1H, J=8 Hz), 7.31 (d, 1H,J=8 Hz), 7.11 (d, 2H, J=9 Hz), 7.04 (t, 1H, J=7 Hz), 6.95 (t, 1H, J=7Hz), 6.38 (S, 1 h), 4.09 (t, 2H, J=6 Hz), 4.02 (s, 4H), 2.36 (t, 2H, J=7Hz), 2.15 (s, 6H), 1.87 (m, 2H). IR (KBr, cm⁻¹) 3425, 3050, 2942, 2757,1617, 1499, 1256, 1175, 732. MS (ES⁺) m/e 423. MS (ES⁻) m/e 421. Anal.Calcd for C₂₃H₂₆N₄O₂S C, 65.38; H, 6.20; N, 13.26. Found C, 65.00; H,6.17; N, 13.12.

Example 194 Preparation of(3-{4-[5-(1H-Benzoimidazol-2-ylmethylsulfanylmethyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamine

a) 2-Chloromethylbenzoimidazole-1-carboxylic acid tert-butyl ester

A mixture of 2-(chloromethyl)benzimidazole (4.05 g, 24.3 mmol),4-dimethylamino pyridine (0.297 g, 2.4 mmol) and di-tert-butyldicarbonate (6.37 g, 29.2 mmol) in 48 ml CH₃CN was stirred at roomtemperature for four hours. Next, the suspension was heated at 60 C for30 minutes. Upon cooling to room temperature the mixture wasconcentrated to an oil. The mixture was treated with 100 ml each of 1NHCl and Et₂O and the resultant suspension was filtered. The phases fromthe filtrate were separated and the organic phase was washed with 1N HCl(2×100 ml), brine then concentrated to an oil. Purification by normalphase chromatography (eluted with 70% hexane:EtOAc) afforded 2.23 g(34%) of 2-chloromethylbenzoimidazole-1-carboxylic acid tert-butyl esteras an oil.

H NMR (DMSO-d6)

8.06 (d, 1H, J=10 Hz), 7.61 (d, 1H, J=8 Hz), 7.21–7.37 (m, 2H), 7.00 (s,1H), 5.99 (s, 2H), 4.05 (s, 3H). IR (KBr, cm⁻¹) 3455, 2980, 2934, 2869,1709, 1606, 1509, 1454, 1367, 1244, 1169. Anal. Calcd for C₁₃H₁₅ClN₂O₂C, 58.54; H, 5.67; N, 10.50. Found C, 58.55; H, 5.93; N, 10.42.

b)(3-{4-[5-(1H-benzoimidazol-2-ylmethylsulfanylmethyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.264 g, 0.7 mmol), lithium hydroxide (0.032 g, 1.3 mmol) and2-chloromethylbenzoimidazole-1-carboxylic acid tert-butyl ester (0.178g, 0.7 mmol) in 1 ml MeOH to afford 0.118 g of an oil. The oil wasdissolved into acetone and treated with 0.038 g of oxalic acid inacetone to afford 0.121 g (36%) of(3-{4-[5-(1H-benzo-imidazol-2-ylmethyl-sulfanylmethyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamine as the dioxalate salt.

¹H NMR (DMSO-d6)

11.11 (bs, 1H), 7.84 (d, 2H, J=9 Hz), 7.44 (d, 1H, J=8 Hz), 7.31 (d, 1H,J=8 Hz), 7.11 (d, 2H, J=9 Hz), 7.04 (t, 1H, J=7 Hz), 6.95 (t, 1H, J=7Hz), 6.38 (s, 1H), 4.09 (t, 2H, J=6 Hz), 4.02 (s, 4H), 2.36 (t, 2H, J=7Hz), 2.15 (s, 6 h), 1.87 (m, 2H). IR (KBr, cm⁻¹) 3425, 3050, 2942, 2757,1617, 1499, 1256, 1175, 732. MS (ES⁺) m/e 424. MS (ES) m/e 422.

Example 195 Preparation of(3-{4-[5-Benzofuran-3-ylmethylsulfanyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.622 g, 1.6 mmol), lithium hydroxide (0.075 g, 3.1 mmol) and3-bromomethylbenzofuran (0.331 g, 1.6 mmol) in 2.3 ml MeOH.Crystallization from Et₂O afforded 0.202 g (30%) of(3-{4-[5-benzofuran-3-ylmethylsulfanyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethyl-amine.

¹H NMR DMSO-d6)

7.95 (s, 1H), 7.83 (d, 2H, J=9 Hz), 7.72 (m, 1H), 7.54 (d, 1H, J=8 Hz),7.23–7.43 (m, 2H), 7.11 (D, 2 h, J=9 Hz), 4.09 (t, 2H, J=7 Hz), 4.03 (s,2H), 4.01 (s, 2H), 2.36 (t, 2H, J=7 Hz), 2.14 (s, 6H), 1.83–1.92 (m,2H). IR (KBr, cm⁻¹) 2817, 2766, 1611, 1502, 1472, 1452, 1302, 1258,1179, 1101, 1089, 1004, 839, 746. MS (ES⁺) m/e 424. Anal. Calcd forC₂₃H₂₅N₃O₃S C, 65.23; H, 5.95; N, 9.92. Found C, 65.27; H, 6.22; N,9.65. Mp (° C.)=85.

Example 196 Preparation of(3-{4-[5-Benzylsulfanylmethyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.220 g, 0.5 mmol), lithium hydroxide (0.026 g, 1.1 mmol) and benzylbromide (0.095 g, 0.6 mmol) in 0.9 ml MeOH to afford 0.087 g (41%) of(3-{4-[5-Benzylsulfanylmethyl)-[1,3,4]-oxadiazol-2-yl]phenoxy}propyl)dimethylamineas a crystalline solid.

¹H NMR (DMSO-d6)

7.89 (d, 2H, J=9 Hz), 7.21–7.38 (m, 5H), 7.12 (d, 2H, J=9 Hz), 4.09 (t,2H, J=6 Hz), 3.95 (s, 2H), 3.86 (s, 2H), 2.36 (t, 2H, J=7 Hz), 2.15 (s,6H), 1.83–1.92 (m, 2H). IR (KBr, cm⁻¹) 2761, 1614, 1565, 1499, 1473,1246, 1175, 1049, 838, 701. MS (ES⁺) m/e 384. Anal. Calcd forC₂₁H₂₅N₃O₃S C, 65.77; H, 6.57; N, 10.96. Found C, 65.54; H, 6.50; N,10.83.

Example 197 Preparation ofDimethyl-(3-{4-[5-(quinolin-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.344 g, 0.9 mmol), lithium hydroxide (0.062 g, 2.6 mmol) and2-chloromethyl quinoline HCl (0.184 g, 0.9 mmol) in 1.4 ml MeOH toafford 0.182 g of an oil. A solution of ethanol (0.194 g, 4.2 mmol) inEt₂O was treated with acetyl chloride (0.131 g, 1.7 mmol) to generateHCl in situ. After stirring five minutes this solution was added to asolution of the title compound in Et2O. The resultant suspension wasfiltered to afford 0.204 g (50%) ofdimethyl-(3-{4-[5-(quinolin-2-ylmethylsulfanyl-methyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)aminemonohydrochlroride salt.

¹H NMR (DMSO-d6)

8.30 (d, 1H, J=8 Hz), 7.90–7.94 (m, 2H), 7.78 (d, 2H, J=9 Hz), 7.69–7.75(m, 1H), 7.53–7.60 (m, 2H), 7.09 (d, 2H, J=9 Hz), 4.15–4.18 (m, 6H),3.19–3.24 (m, 2H), 2.78 (s, 6H), 2.13–2.23 (m, 2H). IR (KBr, cm⁻¹) 2954,2632, 2607, 2483, 1615, 1499, 1486, 1473, 1260, 1242, 1183, 837, 827,759. MS (ES⁺) m/e 435. Anal. Calcd for C₂₄H₂₆N₄O₂S HCl C, 61.20; H,5.78; N, 11.89. Found C, 60.86; H, 5.77; N, 11.90. Mp(° C.)=190.

Example 198 Preparation of(3-{4-[5-(Biphenyl-4-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.207 g, 0.5 mmol), lithium hydroxide (0.025 g, 1.0 mmol) and4-bromomethylbiphenyl (0.129 g, 0.5 mmol). After stirring at roomtemperature for three hours the suspension was filtered. The insolublematerial was dissolved into EtOAc:MeOH and purified by normal phasesilica gel chromatography (eluted with 5% 2M NH₃ in MeOH:CH₂Cl₂) toafford a white solid. This material was then converted to the HCl asdescribed in Example 5 using the acetyl chloride/EtOH method to generateHCl in situ to afford 0.112 g (43%) of(3-{4-[5-(Biphenyl-4-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethyl-amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.88 (d, 2H, J=9 Hz), 7.59 (d, 4H, J=8 Hz), 7.33–7.47 (m, 5H), 7.11 (d,2H, J=9 Hz), 4.14 (t, 2H, J=6 Hz), 4.00 (s, 2H), 3.91 (s, 2H), 3.19–3.24(m, 2H), 2.78 (s, 6H), 2.13–2.22 (m, 2H).IR (KBr, cm⁻¹) 3491, 2956,2599, 2470, 1617, 1587, 1566, 1501, 1484, 1428, 1393, 1308, 1258, 1171,1087, 1054, 1003, 834, 695. MS (ES⁺) m/e 460. Analytical HPLC: 100%.Mp(° C.)=191.

Example 199 Preparation of(3-{4-[5-(4-Benzyl-benzylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.206 g, 0.5 mmol), lithium hydroxide (0.025 g, 1.0 mmol) and4-benzyl-benzylmethyl bromide (0.135 g, 0.5 mmol) in 1 ml MeOH.Purification by normal phase silica gel chroma-tography (eluted with 5%2M NH₃ in MeOH:CH₂Cl₂ to 10% 2M NH₃ in MeOH:CH₂Cl₂) afforded an oil.This material was then converted to the HCl as described in Example 5using the acetyl chloride/EtOH method to generate HCl in situ to afford0.073 g (28%) of(3-{4-[5-(4-Benzyl-benzylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)di-methylamine as the hydrochloride salt.

¹H NMR (DMSO-d6)

7.90 (d, 2H, J=9 Hz), 7.11–7.32 (m, 11H), 4.16 (t, 2H, J=6 Hz) 3.94 (s,2H), 3.88 (s, 2H), 3.82 (s, 2H), 3.22 (t, 2H, J=8 Hz), 2.77 (s, 6H),2.13–2.23 (m, 2H). IR (KBr, cm⁻¹) 3482, 3024, 2933, 2599, 2475, 1616,1500, 1428, 1307, 1257, 1173, 1053, 1002, 835, 724, 699. MS (ES⁺) m/e474. Mp(° C.)=151.

Example 200 Preparation of(3-{4-[5-(2,2-diphenylethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.233 g, 0.6 mmol), lithium hydroxide (0.028 g, 1.2 mmol) and2,2-diphenylethylbromide (0.153 g, 0.6 mmol). The reaction was stirredat room temperature for 3 hours then heated at 60 C for 2 two days.Purification by normal phase silica gel chroma-tography (eluted with 5%2M NH₃ in MeOH:CH₂Cl₂ to 10% 2M NH₃ in MeOH:CH₂Cl₂) afforded an oil.This material was then converted to the HCl as described in Example 5using the acetyl chloride/EtOH method to generate HCl in situ to afford0.104 g (35%) of(3-{4-[5-(2,2-diphenylethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.88 (d, 2H, J=9 Hz), 7.23–7.31 (m, 8H), 7.12–7.18, m, 4H), 4.22 (t, 1H,J=8 Hz), 4.16 (t, 2H, J=6 Hz), 4.09 (s, 2H), 3.35 (d, 2H, J=8 Hz), 3.21(t, 2H, J=8 Hz), 2.77 (s, 6H), 2.08–2.21 (m, 2H). IR (KBr, cm⁻¹) 3436,3024, 2954, 2594, 2478, 1734, 1613, 1568, 1501, 1452, 1302, 1259, 1176,1051, 839, 734, 706, 530. MS (ES⁺) m/e 474. Mp(° C.)=149.

Example 201 Preparation of(3-{4-[5-(Benzofuran-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of 193c, from thiobenzoic acidS-{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}ester(0.633 g, 1.4 mmol), lithium hydroxide (0.069 g, 2.9 mmol) andbenzofuran-2-ylmethyl bromide (0.305 g, 1.4 g). Crystallization of theisolated product from Et₂O afforded 0.246 g (37%) of(3-{4-[5-(Benzofuran-2-ylmethyl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine.

¹H NMR (DMSO-d6)

7.79 (d, 2H, J=9 Hz), 7.52 (d, 1H, J=7 Hz), 7.44 (d, 1H, J=8 Hz),7.16–7.24 (m, 2H), 7.07 (d, 2H, J=9 Hz), 6.78 (s, 1H), 4.07–4.13 (m,6H), 2.27–2.40 (m, 6H), 1.85–1.91 (m, 2H), 1.45–1.52 (m, 4H), 1.34–1.40(m, 2H). IR (KBr, cm⁻¹) 2933, 2769, 1611, 1501, 1452, 1393, 1300, 1249,1174, 1130, 1089, 1049, 1005, 950, 839, 815, 761. MS (ES⁺) m/e 464.Anal. Calcd for C₂₆H₂₉N₃O₃S C, 67.36; H, 6.31; N, 9.00. Found C, 67.50;H, 6.52; N, 9.03. Mp(° C.)=114.

Example 202 Preparation of(3-{4-[5-(Benzofuran-2-ylmethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy]propyl)dimethylamine

a) {5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol

To a solution of acetoxy acetic acid (0.249 g, 2.1 mmol) in 9 ml THF atroom temperature was added 1,1′-carbonyldiimidazole (0.342 g, 2.1 mmol).The solution was heated at 60 C for 80 minutes, the stirred at roomtemperature for 40 minutes. The solution was then treated with4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (0.500 g, 2.1 mmol).The resultant light suspension was stirred at room temperature for 1.5hours. Next, the suspension was treated with triphenyl phosphine (1.11g, 4.2 mmol) and carbon tetrabromide (1.40 g, 4.2 mmol). The reactionwas stirred an additional three hours before being concentrated to asemi-solid material. The crude material was treated with 5.4 ml MeOH and1.6 ml H₂O then lithium hydroxide (0.151 g, 6.3 mol) was added. Afterstirring at room temperature for 1.45 hours the reaction wasconcentrated in volume then extracted three times with EtOAc. Thecombined organic phases were washed with brine, dried over Na₂SO₄,filtered, then concentrated to an oil. Purification by normal phasesilica gel radial chromatography (eluted with 9:1 CHCl₃:2M NH₃ in MeOH)afforded 0.339 g (58%) of{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol.

¹H NMR (DMSO-d6)

7.92 (d, 2H, J=9 Hz), 7.13 (d, 2H, J=9 Hz), 5.92 (t, 1H, J=6 Hz), 4.68(d, 2H, J=6 Hz), 4.09 (t, 2H, J=6 Hz), 2.36 (t, 2H, J=7 Hz), 2.12 (s,6H), 1.83–1.92 (m, 2H). IR (KBr, cm⁻¹) 2873, 2788, 1613, 1588, 1500,1467, 1309, 1258, 1179, 1055, 1003, 742, 675, 534. MS (ES⁺) m/e 278.

b)(3-{4-[5-(Benzofuran-2-ylmethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)-dimethylamine

To a solution of{5-[4-(3-dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol(0.150 g, 0.5 mmol) in 2.5 ml DMF at room temperature was added 60%sodium hydride (0.023 g, 0.6 mmol). After stirring at room temperaturefor one hour an additional 2 ml DMF was added followed by2-(bromomethyl)naphthalene (0.120 g, 0.5 mmol). Approximately one hourlater additional 60% sodium hydride (0.023 g, 0.6 mmol) was added. Thereaction was treated with H₂O and extracted three times with EtOAc. Thecombined organic phases were washed with brine, dried over Na₂SO₄,filtered, and concentrated to an oil. Purification by normal phasesilica gel radial chromatography (eluted with 95:5 CHCl₃:2M NH₃ in MeOH)to afford an oil. This material was then converted to the HCl asdescribed in Example 5 using the acetyl chloride/EtOH method to generateHCl in situ to afford 0.063 g (26%) of(3-{4-[5-(Benzofuran-2-ylmethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethyl-amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.88–7.97 (m, 6H), 7.49–7.55 (m, 3H), 7.15 (d, 2H, J=9 Hz), 4.88 (s,2H), 4.82 (s, 2H), 4.17 (t, 2H, J=6 Hz), 3.22 (t, 2H, J=8 Hz), 2.76 (s,6H), 2.13–2.23 (m, 2H). IR (KBr, cm⁻¹) 2472, 1616, 1500, 1472, 1257,1089. MS (ES⁺) m/e 418. Anal. Calcd for C₂₅H₂₇N₃O₃ HCl C, 66.14; H,6.22; N, 9.26. Found C, 65.74; H, 6.11; N, 9.14. Mp(° C.)=173.

Example 203 Preparation ofDimethyl-{3-[4-(5-naphthalene-2-yl-[1,3,4]oxadiazol-2-yl)phenoxy]-25propyl}amine

a) 4-Hydroxybenzoic acid N′-(naphthalene-2-carbonyl)hydrazide

To a solution of 2-naphthaoic acid (2.01 g, 11.7 mmol) in 30 ml DMF at 0C was added fluoro-N,N,N′-tetramethylformamidinium hexafluoro phosphate(3.08 g, 11.7 mmol). The reaction was stirred at 0 C for fifteen minutesthen triethylamine (2.36 g, 23.3 mmol) and a suspension of4-hydroxybenzoic hydrazide (3.55 g, 23.3 mmol) in 30 ml DMF, were added.The reaction was then stirred at room temperature for thirty minutes.Next, the resultant solution was slowly poured into 600 ml of ice water.The resultant suspension was filtered. The insoluble material wastriterated in 500 ml 5N HCl until a fine suspension resulted. Theinsoluble material was collected by filtration then treated with 300 mlboiling MeOH. The milky suspension was filtered and the filtrate wasreduced in volume on a steam bath until crystals started forming. Thecrystalline material was collected by filtration to afford 1.63 g (46%)of 4-Hydroxybenzoic acid N′-(naphthalene-2-carbonyl)hydrazide.

¹H NMR (DMSO-d6)

10.55 (s, 1H), 10.30 (s, 1H), 10.11 (s, 1H), 8.55 (s, 1H), 7.97–8.08 (m,4H), 7.82 (d, 2H, J=8 Hz), 7.59–7.68 (m, 2H), 6.86 (d, 2H, J=8 Hz). IR(KBr, cm⁻¹) 3339, 1734, 1676, 1645, 1583, 1506, 1437, 1377, 1276, 1238,1170, 779, 757, 547, 478. MS (ES⁻) m/e 305.

a) 4-(5-Naphthalen-2-yl-[1,3,4]oxadiazol-2-yl)phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-Hydroxybenzoic acidN′-(naphtha-lene-2-carbonyl)hydrazide (1.57 g, 5.1 mmol),triphenylphosphine (2.69 g, 10.3 mmol), triethylamine (1.66 g, 16.4mmol) and carbon tetrabromide (3.40 g, 10.3 mmol) to afford an oil. Theoil was treated with 100 ml EtOAc. The resultant precipitate wascollected by filtration and discarded. The filtrate was concentrated toan oil. Purification by normal phase silica gel chromatography (elutedwith 3:2 hexane:EtOAc) afforded 0.220 g (15%) of4-(5-Naphthalen-2-yl-[1,3,4]oxadiazol-2-yl)phenol.

¹H NMR (DMSO-d6)

10.36 (s, 1H), 8.74 (s, 1H), 8.13–8.18 (m, 3H), 8.01–8.08 (m, 3H),7.64–7.70 (m, 2H), 7.01 (d, 2H, J=9 Hz). IR (KBr, cm⁻¹) 1735, 1610,1589, 1504, 1443, 1292, 1171, 844, 751. MS (ES⁺) m/e 289, MS (ES⁻) m/e287

c)Dimethyl-{3-[4-(5-naphthalene-2-yl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-(5-naphthalen-2-yl-[1,3,4]oxadiazol-2-yl)phenol (0.205 g, 0.7 mmol),sodium hydride (0.057 g, 1.4 mmol) and 3-chloro-N,N-dimehtylpropyl amineHCl (0.112 g, 0.7 mmol) to afford the title compound as a crudematerial. Purification by radial chromatography on silica gel (elutedwith 9:1 Et₂O: 2M NH₃ in MeOH) afforded 0.120 g (45%) ofdimethyl-{3-[4-(5-naphthalene-2-yl-[1,3,4]-oxadiazol-2-yl)phenoxy]propyl}amineas a solid.

¹H NMR (DMSO-d6)

8.76 (s, 1H), 8.01–8.21 (m, 6H), 7.64–7.70 (m, 2H), 7.18 (d, 2H, J=9Hz), 4.13 (t, 2H, J=6 Hz), 2.38 (t, 2H, J=7 Hz), 2.13 (s, 6H), 1.85–1.94(m, 2H). IR (KBr, cm⁻¹) 1613, 1498, 1464, 1257, 1175. MS (ES⁺) m/e 374.Mp(° C.)=127.

Example 204 Preparation ofDimethyl-{3-[4-(5-naphthalene-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-phenoxy]propyl}amine

a) 4-(3-Dimethylaminopropoxy)benzoic acidN′-(2-naphthalen-2-ylacetyl)hydrazide

To a solution of 2-naphthyl acetic acid (0.237 g, 1.3 mmol) in 5.6 mlTHF at room temperature was added 1,1′-carbonyldiimidazole (0.206 g, 1.3mmol). The solution was heated at 60 C for one hour. Upon cooling toroom temperature, the reaction was treated with4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (0.302 g, 1.3 mmol).The reaction was stirred at room temperature for four hours thenconcentrated to an oil. The oil was treated with 25 ml 0.1 N NaOH andextracted with EtOAc (2×25 ml). A precipitate develop in the aqueousphase. The precipitate was collected by filtration to afford 0.306 g(59%) of 4-(3-Dimethylaminopropoxy)benzoic acidN′-(2-naphthalen-2-ylacetyl)hydrazide.

¹H NMR (DMSO-d6)

10.21 (bs, 2H), 7.81–7.91 (m, 6H), 7.45–7.53 (m, 3H), 6.99 (d, 2H, J=9Hz), 4.05 (t, 2H, J=6 Hz), 3.71 (s, 2H), 2.34 (t, 2H, J=7 Hz), 2.10 (s,6H), 1.80–1.89 (m, 2H). IR (CHCl₃, cm⁻¹) 1682, 1631, 1608, 1510, 1463,1255, 1174. MS (ES⁺) m/e 406, MS (ES⁻) m/e 404.

b)Dimethyl-{3-[4-(5-naphthalene-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-phenoxy]propyl}-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-Dimethylaminopropoxy)benzoic acidN′-(2-naphthalen-2-ylacetyl)hydrazide (0.436 g, 1.1 mmol),triphenylphosphine (0.564 g, 2.2 mmol), triethylamine (0.218 g, 2.2mmol) and carbon tetrabromide (0.713 g, 2.2 mmol) to afford an oil.Purification by normal phase silica gel chromatography (eluted with 9:1Et₂O:2M NH₃ in MeOH) followed by conversion to the HCl salt as describedin Example 5 using the acetyl chloride/EtOH method to generate HCl insitu afforded 0.235 g (52%) ofdimethyl-{3-[4-(5-naphthalene-2-ylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.87–7.94 (m, 6H), 7.48–7.55 (m, 3H), 7.12 (d, 2H, J=9 Hz), 4.51 (s,2H), 4.14 (t, 2H, J=6 Hz), 3.20 (t, 2H, 8 Hz), 2.74 (s, 6H), 2.11–2.20(m, 21). IR (KBr, cm⁻¹) 3442, 2954, 2673, 2614, 2476, 1616, 1588, 1501,1477, 1254, 1178, 1254, 1178, 836, 784, 739, 490. MS (ES⁺) m/e 388. Mp(°C.)=192.

Example 205 Preparation ofDimethyl-{3-[4-(5-naphthalene-2-ylethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amine

a) 4-Hydroxybenzoic acid N-(3-naphthalen-2-yl-propionyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 26b, from 3-naphthalen-2-yl proprionicacid (1.00 g, 5.0 mmol), 1,1′-carbonyldiimidazole (0.810 g, 5.0 mmol)and 4-hydroxybenzoic hydrazide (0.760 g, 5.0 mmol) to afford an oil thatcrystallizes out. This material was triterated in EtOAc, filtered toafford 0.320 g (10%) of 4-hydroxybenzoic acidN-(3-naphthalen-2-yl-propionyl)hydrazide along with an impurity.

¹H NMR (DMSO-d6)

7.76–7.90 (m, 6H), 7.40–7.50 (m, 3H), 7.15–7.20 (m, 2H), 3.14–3.18 (m,2H), 2.56–2.65 (m, 2H). MS (ES⁻) m/e 333.

b) 4-[5-(2-Naphthalen-2-yl-ethyl)-[1,3,4]oxadizol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoic acidN-(3-naphthalen-2-yl-propionyl)hydrazide (0.320 g, 1.0 mmol),triphenylphosphine (0.502 g, 2.0 mmol), triethylamine (0.310 g, 3.1mmol) and carbon tetrabromide (0.635 g, 2.0 mmol). Purification bynormal phase silica gel radial chromatography (eluted with 3:1EtOAc:hexane) followed by crystallization from EtOAc afforded 0.277 g(91%) of 4-[5-(2-Naphthalen-2-yl-ethyl)-[1,3,4]oxadizol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.26 (bs, 1H), 7.73–7.88 (m, 6H), 7.43–7.51 (m, 3H), 6.91 (d, 2H, J=8Hz), 3.23–3.36 (m, 4H). IR (KBr, cm⁻¹) 3051, 3016, 1603, 1579, 1505,1443, 1282, 1239, 1170. MS (ES⁺) m/e 317, MS (ES) m/e 315. Anal. Calcdfor C₂₀H₁₆N₂O₂ C, 75.93; H, 5.10; N, 8.85. Found C, 75.60; H, 5.14; N,8.70.

d)Dimethyl-{3-[4-(5-naphthalene-2-ylethyl)-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-[5-(2-Naphthalen-2-yl-ethyl)-[1,3,4]oxadizol-2-yl]phenol (0.388 g, 1.1mmol), sodium hydride (0.085 g, 2.1 mmol) and3-chloro-N,N-dimehtylpropyl amine HCl (0.169 g, 1.1 mmol). Purificationby radial chromatography on silica gel (eluted with 9:1 Et₂O: 2M NH₃ inMeOH) followed by conversion to the HCl salt as described in Example 5using the acetyl chloride/EtOH method to generate HCl in situ afforded0.192 g (36%) ofdimethyl-{3-[4-(5-naphthalene-2-ylethyl)-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amineas the hydrochloride salt.

¹H NMR (DMSO-d6) δ7.79–7.91 (m, 6H), 7.43–7.51 (m, 3H), 7.13 (d, 2H, J=9Hz), 4.16 (t, 2H, J=6 Hz), 3.18–3.38 (m, 6H), 2.76 (s, 6H), 2.12–2.21(m, 2H). IR(CHCl₃, cm⁻¹) 2969, 1615, 1501, 1475, 1253, 1176. MS (ES⁺)m/e 402. Mp(° C.)=208–210.

Example 206 Preparation ofdimethyl-{3-[4-(5-naphthalene-2-ylpropyl)-[1,3,4]oxadiazol-2-yl)-phenoxy]propyl}amine

a) 4-Hydroxybenzoic acid N-(4-naphthalen-2-yl-butyryl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 2-naphthalenebutanoic acid(0.600 g, 2.8 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(0.692 g, 2.8 mmol) and 4-hydroxybenzoic hydrazide (0.426 g, 2.8 mmol).Crystallization of the isolated crude material from acetone afforded0.507 g (52%) of 4-Hydroxybenzoic acidN-(4-naphthalen-2-yl-butyryl)hydrazide.

¹H NMR (DMSO-d6)

10.11 (bd, 2H), 9.74 (bs, 1H), 7.84–7.89 (m, 31), 7.70–7.77 (m, 3H),7.35–7.50 (m, 3H), 6.81 (d, 2H, J=8 Hz), 2.81 (t, 2H, J=7 Hz), 2.23 (t,2H, J=7 Hz), 1.93–2.00 (m, 2H). IR (KBr, cm⁻¹) 3312, 3270, 3015, 1662,1624, 1608, 1504, 1321, 1279, 1228, 849, 664, 475. MS (ES⁻) m/e 347.Anal. Calcd for C₂₁H₂₀N₂O₃ C, 72.40; H, 5.79; N, 8.04. Found C, 72.04;H, 5.65; N, 7.92.

b) 4-[5-(3-Naphthalen-2-yl-propyl)-[1,3,4]oxadiazol-2-yl)phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoic acidN-(4-naph-thalen-2-yl-butyryl)hydrazide (0.464 g, 1.3 mmol),triphenylphosphine (0.699 g, 2.7 mmol), triethylamine (0.270 g, 2.7mmol) and carbon tetrabromide (0.883 g, 2.7 mmol). Purification bynormal phase silica gel radial chromatography (eluted with EtOAc)afforded 4-[5-(3-naphthalen-2-yl-propyl)-[1,3,4]oxadiazol-2-yl)phenol asa solid.

¹H NMR (DMSO-d6)

10.25 (bs, 1H), 7.72–7.88 (m, 6H), 7.41–7.51 (m, 3H), 6.92 (d, 2H, J=9Hz), 2.86–2.96 (m, 4H), 2.11–2.21 (m, 2H). IR (KBr, cm⁻¹) 1613, 1600,1502, 1285, 1236, 1175, 856, 820, 746, 473. MS (ES⁺) m/e 331, MS (ES⁻)m/e 329.

c)Dimethyl-{3-[4-(5-naphthalene-2-ylpropyl)-[1,3,4]oxadiazol-2-yl)-phenoxy]propyl}amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(3-naphthalen-2-yl-propyl)-[1,3,4]oxadiazol-2-yl)phenol (0.252 g,0.8 mmol), cesium carbonate (0.497 g, 1.5 mmol), and3-chloro-N,N-dimethylpropylamine HCl (0.121 g, 0.8 mmol). Purificationby normal phase silica gel radial chromatography (eluted with 95:5CHCl₃:2M NH₃ in MeOH) followed by crystallization from Et₂O afforded0.071 g (22%) ofdimethyl-{3-[4-(5-naphthalene-2-ylpropyl)-[1,3,4]oxadiazol-2-yl)-phenoxy]propyl}amine.

¹H NMR (DMSO-d6)

7.84–7.89 (m, 5H), 7.74 (s, 1H), 7.42–7.51 (m, 3H), 7.10 (d, 2H, J=9Hz), 4.08 (t, 2H, J=6 Hz), 2.86–2.98 (m, 4H), 2.36 (t, 2H, J=7 Hz),2.11–2.20 (m, 8H), 1.82–1.91 (m, 2H). IR (KBr, cm⁻¹) 2950, 2817, 2768,1916, 1587, 1503, 1255, 1172, 1004, 845, 744. MS (ES⁺) m/e 416. Anal.Calcd for C₂₆H₂₉N₃O₂ C, 75.15; H, 7.03; N, 10.11. Found C, 75.01; H,6.89; N, 10.02, Mp(° C.)=92.

Example 207 Preparation ofdimethyl-{3-[4-(5-naphthalene-2-ylbutyl)-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amine

a) 4-(3-Dimethlaminopropoxy)benzoic acidN-(5-naphthalen-2-ylpentanoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 204a, from 2-naphthalenepentanoic acid(0.600 g, 2.6 mmol), 1,1′-carbonyldiimidazole (0.426 g, 2.6 mmol) and4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (0.624 g, 2.6 mmol).The reaction suspension was filtered to afford 0.417 g (35%) of4-(3-Dimethlaminopropoxy)benzoic acidN-(5-naphthalen-2-ylpentanoyl)hydrazide.

¹H NMR (DMSO-d6)

10.04 (bs, 1H), 9.74 (bs, 1H), 7.79–7.88 (m, 5H), 7.71 (s, 1H),7.38–7.50 (m, 3H), 6.99 (d, 2H, J=9 Hz), 4.05 (t, 2H, J=6 Hz), 2.78 (t,2H, J=7 Hz), 2.34 (t, 2H, J=7 Hz), 2.23 (t, 2H, J=7 Hz), 2.13 (s, 6H),1.81–1.89 (m, 2H), 1.58–1.76 (m, 4H). IR (KBr, cm⁻¹) 3203, 2935, 2855,2762, 1665, 1598, 1568, 1465, 1256, 1173, 843, 818, 474. MS (ES⁺) m/e448, MS (ES) m/e 446. Anal. Calcd for C₂₇H₃₃N₃O₃ C, 72.46; H, 7.43; N,9.39. Found C, 72.51; H, 7.46; N, 9.20.

b)Dimethyl-{3-[4-(5-naphthalene-2-ylbutyl)-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-Dimethlaminopropoxy)benzoic acidN-(5-naphthalen-2-ylpentanoyl)hydrazide (0.303 g, 0.68 mmol),triphenylphosphine (0.355 g, 1.4 mmol), triethylamine (0.137 g, 1.4mmol) and carbon tetrabromide (0.449 g, 1.4 mmol. Purification by normalphase silica gel chromatography (eluted with 9:1 CHCl₃:2M NH₃ in MeOH)followed by conversion to the HCl salt, as described in Example 5 usingthe acetyl chloride/EtOH method to generate HCl in situ, afforded thetitle compound. Crystallization from Et2O:MeOH afforded 0.080 g (7%) ofdimethyl-{3-[4-(5-naphthalene-2-ylbutyl)-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amine.

¹H NMR (DMSO-d6) δ 7.82–7.92 (m, 5H), 7.70 (s, 1H), 7.38–7.50 (m, 3H),7.11 (d, 2H, J=9 Hz), 4.15 (t, 2H, J=6 Hz), 3.21 (t, 2H, J=8 Hz),2.94–2.99 (m, 2H), 2.76–2.84 (m, 8H), 2.12–2.21 (m, 2H), 1.79–1.81 (m,4H). R (KBr, cm⁻¹) 2936, 1613, 1502, 1256, 1256, 1175. MS (ES⁺) m/e 430.Mp(° C.)=195.

Example 208 Preparation of4-{5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2yl}-1-naphthalen-2yl-butan-1-one

a) 4-(3-Dimethylaminopropoxy)benzoic acidN-(5-naphthalen-2-yl-5-oxopentanoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 204a, from 4-(2-naphthoyl)butyric acid(0.705 g, 2.9 mmol), 1,1′-carbonyldiimidazole (0.472 g, 2.9 mmol) and4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (0.691 g, 2.9 mmol).After stirring 6.5 hours at room temperature the reaction mixture wasconcentrated to an oil. The oil was treated with 25 ml each of EtOAc andH₂O. Crystals that formed in this mixture were collected by filtrationto afford 0.536 g (40%) of the title compound. The filtrate wasconcentrated to a solid. Purification by normal phase silica gel radialchromatography (eluted with 9:1 CHCl₃:2M NH₃ in MeOH) afforded 0.120 g(9%) of the title compound. 0.656 g (49%) of4-(3-dimethylaminopropoxy)benzoic acidN-(5-naphthalen-2-yl-5-oxopentanoyl)hydrazide was collected.

¹H NMR (DMSO-d6)

10.15 (bs, 1H), 9.84 (bs, 1H), 8.72 (s, 1H), 8.13 (m, 1H), 7.97–8.06 (m,3H), 7.84 (d, 2H, J=9 Hz), 7.60–7.70 (m, 21), 7.00 (d, 2H, J=9 Hz), 4.06(t, 2H, J=6 Hz), 3.26–3.32 (m, 2H), 2.30–2.37 (m, 41), 2.11 (s, 6H),1.93–2.02 (m, 2H), 1.81–1.88 (m, 2H). IR (KBr, cm⁻¹) 3422, 3252, 2949,2792, 1683, 1644, 1604, 1504, 1468, 1251, 1178, 1122, 758. MS (ES⁺) m/e462, MS (ES⁻) m/e 460.

b)4-{5-[4-(3-Dimethylaminopropoxy)phenyl]-[1,3,4]oxadiazol-2yl}-1-naphthalen-2yl-butan-1-one

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-dimethylaminopropoxy)benzoic acidN-(5-naphthalen-2-yl-5-oxopentanoyl)hydrazide (0.334 g, 0.72 mmol),triphenylphosphine (0.380 g, 1.5 mmol), triethylamine (0.146 g, 1.5mmol) and carbon tetrabromide (0.480 g, 1.5 mmol. Purification by normalphase silica gel chromatography (eluted with 9:1 CHCl₃:2M NH₃ in MeOH)followed by conversion to the HCl salt, as described in Example 5 usingthe acetyl chloride/EtOH method to generate HCl in situ, afforded 0.119g (34%) of4-{5-[4-(3-dimethylaminopropoxy)-phenyl]-[1,3,4]oxadiazol-2yl}-1-naphthalen-2yl-butan-1-one.

¹H NMR (DMSO-d6)

8.68 (s, 1H), 8.12 (d, 1H, J=7 Hz), 7.97–8.06 (m, 3H), 7.90 (d, 2H, J=9Hz), 7.60–7.71 (m, 2H), 7.10 (d, 2H, J=9 Hz), 4.15 (t, 2H, J=6 Hz), 3.37(t, 2H, J=7 Hz), 3.21 (t, 2H, J=8 Hz), 3.05 (t, 2H, J=7 Hz), 2.76 (s,6H), 2.13–2.24 (m, 4H). IR (CHCl₃, cm⁻¹) 2969, 1681, 1615, 1501, 1254,1176. MS (ES⁺) m/e 444. Mp(° C.)=211.

Example 209 Preparation of(3-{4-[5-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}-propyl)dimethylamine

a) 4-Hydroxybenzoic acid N-(5-benzofuran-2-yl pentanoyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 5-benzofuran-2-yl-pentanoicacid (2.04 g, 9.3 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(2.31 g, 9.3 mmol) and 4-hydroxybenzoic hydrazide (1.42 g, 9.3 mmol).Purification by normal phase silica gel chromatography (eluted withlinear gradient of 2 to 10% 2M NH₃ in MeOH:CH₂Cl₂) to afford 1.77 g(54%) of 4-hydroxybenzoic acid N-(5-benzofuran-2-yl pentanoyl)hydrazideas a foam.

¹H NMR (DMSO-d6)

10.06 (bs, 1H), 10.00 (bs, 1H), 9.74 (s, 1H), 7.73 (d, 2H, J=9 Hz),7.45–7.56 (m, 2H), 7.15–7.24 (m, 2H), 6.80 (d, 2H, J=9 Hz), 6.60 (s,1H), 2.78–2.83 (m, 2H), 2.23 (t, 2H, J=7 Hz), 1.59–1.80 (m, 4H). IR(KBr, cm⁻¹) 3238, 2945, 1686, 1643, 608, 1586, 1503, 1455, 1310, 1253,1173, 752. MS (ES⁺) m/e 353, MS (ES⁻) m/e 351.

b) 4-{5-[4-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoic acidN-(5-benzo-furan-2-yl pentanoyl)hydrazide (1.63 g, 4.6 mmol),triphenylphosphine (2.43 g, 9.3 mmol), imidazole (1.01 g, 14.8 mmol) andcarbon tetrabromide (3.07 g, 9.3 mmol. Purification by normal phasesilica gel chromatography (eluted with 1:1 EtOAc:hexane) followed bycrystallization from acetone afforded 0.479 g (31%) of4-{5-[4-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.26 (bs, 1H), 7.77 (d, 2H, J=8 Hz), 7.45–7.55 (m, 2H), 6.92 (d, 2H,J=8 Hz), 6.61 (s, 1H), 2.96 (t, 2H, J=7 Hz), 2.84 (t, 2H, J=6 Hz),1.76–1.89 (m, 4H). IR (KBr, cm⁻¹) 1616, 1600, 1582, 1447, 1280, 1250,837, 752, 740. MS (ES⁺) m/e 335, MS (ES) m/e 333. Anal. Calcd forC₂₀H₁₈N₂O₃ C, 71.84; H, 5.43; N, 8.38. Found C, 71.95; H, 5.47; N, 8.41.

c)(3-{4-[5-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-{5-[4-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenol (0.669 g, 2.0mmol), sodium hydride (0.160 g, 4.0 mmol) and3-chloro-N,N-dimehtylpropyl amine HCl (0.316 g, 2.0 mmol). Purificationby radial chromatography on silica gel (eluted with 9:1 Et₂O:2M NH₃ inMeOH) followed by conversion to the HCl salt as described in Example 5using the acetyl chloride/EtOH method to generate HCl in situ afforded0.132 g (14%) of(3-{4-[5-Benzofuran-2-ylbutyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)dimethylamineas the hydrochloride salt.

¹H M (DMSO-d6)

7.90 (d, 2H, J=9 Hz), 7.40–7.54 (m, 2H), 7.11–7.24 (m, 4H), 6.61 (s,1H), 4.16 (t, 2H, J=6 Hz), 3.21 (t, 2H, J=8 Hz), 2.98 (t, 2H, J=7 Hz),2.85 (t, 2H, J=7 Hz), 2.78 (s, 6H), 2.12–2.22 (m, 2H), 1.80–1.99 (m,4H). IR (CHCl₃, cm⁻¹) 2967, 1615, 1501, 1474, 1455, 1253, 1176. MS (ES⁺)m/e 420. Analytical HPLC: 100%. Mp(° C.)=200.

Example 210 Preparation ofDimethyl-(3-{4-[5-(naphthalene-2-ylmethanesulfinylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

To a solution ofdimethyl(3-{4-[5-naphthalen-2-ylmethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine(0.187 g, 0.4 mmol) in 4 ml CH₂Cl₂ at room temperature was added aceticacid (5.18 g, 86.2 mmol) and m-chloroperbenzoic acid (0.074 g, 0.4mmol). After stirring thirty minutes the reaction was quenched withNa₂SO₃. The mixture was diluted with H₂O then extracted twice withEtOAc. Purification by normal phase silica gel radial chromatography(eluted with 95:5. CHCl₃:2M NH₃ in MeOH) followed by conversion to theHCl salt as described in Example 5 using the acetyl chloride/EtOH methodto generate HCl in situ afforded 0.062 g (30%) ofdimethyl-(3-{4-[5-(naphthalene-2-ylmethanesulfinylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6)

7.89–7.97 (m, 6H), 7.53–7.56 (m, 3H), 7.15 (d, 2H, J=9 Hz), 4.60–4.77(m, 2H), 4.36–4.48 (m, 2H), 4.17 (t, 2H, J=6 Hz), 3.19–3.24 (m, 2H),2.73 (s, 6H), 2.14–2.23 (m, 2H). IR (KBr, cm⁻¹) 3429, 2954, 2601, 2476,1613, 1498, 1472, 1258, 1177, 1087, 1054, 838, 742. MS (ES⁺) m/e 450.Mp(° C.)=183.

Example 211 Preparation ofDimethyl(3-{4-[5-(naphthalene-2-ylmethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

a)4-[5-(naphthalene-2-ylmethane-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]phenol

To a solution of4-[5-(naphthalene-2-ylmethanesulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.690 g, 2.0 mmol) in 5 ml DMF at room temperature was addedm-chlroperbenzoic acid (1.46 g, 8.5 mmol). The reaction was stirredthree hours at room temperature then quenched with aqueous Na₂SO₃. Themixture was reduced in volume then diluted with H₂O and extracted withEtOAc. The organic layer was washed with brine, dried over Na2SO4,filtered and concentrated to a solid. Crystallization from Et₂O afforded(0.492 g, 65%) of4-[5-(naphthalene-2-ylmethanesulfonylmethyl)-[1,3,4]-oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.37 (bs, 1H), 7.88–8.01 (m, 4H), 7.77 (d, 2H, J=9 Hz), 7.52–7.59 (m,3H), 6.94 (d, 2H, J=9 Hz), 5.12 (s, 2H), 4.94 (s, 2H).IR (KBr, cm⁻¹)2986, 1660, 1614, 1598, 1507, 1498, 1443, 1319, 1284, 1241, 1173, 1137,1120, 839, 751, 484. MS (ES⁺) m/e 381, MS (ES⁻) m/e 379.

b)Dimethyl(3-{4-[5-(naphthalene-2-ylmethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[5-(naphthalene-2-ylmethane-sulfonylmethyl)-[1,3,4]oxadiazol-2-yl]phenol(0.438 g, 1.2 mmol), cesium carbonate (0.750 g, 2.3 mmol), and3-chloro-N,N-dimethylpropylamine HCl (0.182 g, 1.2 mmol). Purificationby normal phase silica gel radial chromatography (eluted with 9:1CHCl₃:2M NH₃ in MeOH) followed by treatment with oxailic acid afforded0.17 mg (3%) ofdimethyl(3-{4-[5-(naphthalene-2-ylmethanesulfonylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amineas the oxalate salt.

¹H NMR (DMSO-d6)

8.01–7.85 (m, 6H), 7.60–7.51 (m, 3H), 7.15–7.20 (m, 2H), 5.14 (s, 2H),4.93 (s, 2H), 4.10–4.18 (m, 2H), 3.13–3.20 (m, 2H), 2.76 9 (s, 6H),2.18–2.08 (m, 2H). IR (KBr, cm⁻¹) 1614, 1501, 1312, 1260, 1181, 1141,844, 707, 484. MS (ES⁺) m/e 466. Mp(° C.)=218.

Example 212 Preparation ofDimethyl(3-{-[5-naphthalen-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

a) 4-hydroxybenzoic acid N-[2-(naphthalene-2-ylsulfanyl)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 26b, from 2-naphthylmercapto acetic acid(1.50 g, 6.9 mmol), 1,1′-carbonyldiimidazole (1.11 g, 6.9 mmol) and4-hydroxybenzoic hydrazide (1.05 g, 6.9 mmol). Crystallization of thecrude material from EtOAc afforded 1.95 g (81%) of 4-hydroxybenzoic acidN-[2-(naphthalene-2-ylsulfanyl)acetyl]hydrazide.

¹H NMR DMSO-d6) δ 10.21 (bs, 2H), 10.08 (bs, 1H), 7.95 (s, 1H),7.85–7.89 (m, 3H), 7.75 (d, 2H, J=9 Hz), 7.42–7.55 (m, 3H), 6.82 (d, 2H,J=9 Hz), 3.89 (s, 2H). IR (KBr, cm⁻¹) 3314, 3213, 3006, 1703, 1621,1605, 1584, 1516, 1282, 1228, 1175, 847, 810, 746, 478. MS (ES⁺) m/e353, MS (ES⁻) m/e 351.

b) 4-[5-naphthalen-2-ylsulfanylmethyl-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from 4-hydroxybenzoic acidN-[2-(naphthalene-2-ylsulfanyl)acetyl]hydrazide (1.81 g, 5.1 mmol),triphenylphosphine (2.69 g, 10.3 mmol), triethylamine (1.87 g, 18.5mmol) and carbon tetrabromide (3.41 g, 10.3 mmol. Purification by normalphase silica gel chromatography (eluted with 8:1 EtOAc:hexane) followedby crystallization from acetone afforded 0.885 g (51%) of4-[5-naphthalen-2-ylsulfanylmethyl-[1,3,4]oxadiazol-2-yl]phenol.

¹H NMR (DMSO-d6)

10.29 (bs, 1H), 8.02 (s, 1H), 7.90 (d, 2H, J=9 Hz), 7.83–7.86 (m, 1H),7.64 (d, 2H, J=9 Hz), 7.48–7.60 (m, 3H), 6.86 (d, 2H, J=9 Hz), 4.62 (s,2H). IR (KBr, cm⁻¹) 1614, 1561, 1497, 1291, 1225, 1175, 1083, 1020, 819,758, 478. MS (ES⁺) m/e 335. Anal. Calcd for C₁₉H₁₄N₂O₂S C, 68.25; H,4.22; N, 8.38. Found C, 68.10; H, 4.02; N, 8.25.

c)Dimethyl(3-{4-[5-naphthalen-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-[5-naphthalen-2-ylsulfanylmethyl-[1,3,4]oxadiazol-2-yl]phenol (0.800g, 2.4 mmol), sodium hydride (0.196 g, 4.9 mmol) and3-chloro-N,N-dimehtylpropyl amine HCl (0.378 g, 2.4 mmol). Purificationby radial chromatography on silica gel (eluted with 9:1 CHCl₃:2M NH₃ inMeOH) followed by crystallization from Et₂O:MeOH afforded 0.204 g (20%)ofdimethyl(3-{4-[5-naphthalen-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine.

¹H NMR (DMSO-d6)

8.02 (s, 1H), 7.90 (d, 2H, J=9 Hz), 7.83–7.88 (m, 1H), 7.74 (d, 2H, J=9Hz), 7.49–7.60 (m, 3H), 7.05 (d, 2H, J=9 Hz), 4.87 (s, 2H), 4.06 (t, 2H,J=6 Hz), 2.34 (t, 2H, J=7 Hz), 2.10 (s, 6H), 1.81–1.90 (m, 2H). IR (KBr,cm⁻¹) 1607, 1502, 1469, 1299, 1255, 1179, 954, 817, 752, 659, 471. MS(ES⁺) m/e 420. Anal. Calcd for C₂₄H₂₅N₃O₂S C, 68.71; H, 6.01; N, 10.02.Found C, 68.45; H, 5.87; N, 9.89. Mp(° C.)=106.

Example 213 Preparation ofdimethyl(3-{4-[5-naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

a) 4-(3-dimethylaminopropoxy)benzoic acidN-[2-(naphthalene-2-yloxy)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 204a, from (2-naphthoxy)acetic acid(0.285 g, 1.4 mmol), 1,1′-carbonyldiimidazole (0.228 g, 1.4 mmol) and4-[(3-dimethylamino)propoxy]-benzoic acid hydrazide (0.334 g, 1.4 mmol).After stirring at room temperature for 24 hours, the insolubles werecollected by filtration to afford (0.373 g, 63%) of4-(3-dimethylaminopropoxy)benzoic acidN-[2-(naphthalene-2-yloxy)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.26 (bs, 2H), 7.80–7.88 (m, 5H), 7.27–7.51 (m, 4H), 7.01 (d, 2H, J=9Hz), 4.78 (s, 2H), 4.07 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=7 Hz), 2.15 (s,6H), 1.82–1.91 (m, 2H). IR (KBr, cm⁻¹) 3212, 3058, 2955, 2829, 2777,1685, 1652, 1607, 1512, 1313, 1260, 1183, 851, 809, 745, 473. MS (ES⁺)m/e 422, MS (ES⁻) m/e 420.

b)Dimethyl(3-{4-[5-naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-dimethylaminopropoxy)benzoic acidN-[2-(naphthalene-2-yloxy)acetyl]hydrazide (0.322 g, 0.8 mmol),triphenyl-phosphine (0.401 g, 1.5 mmol), triethylamine (0.247 g, 2.4mmol) and carbon tetra-bromide (0.507 g, 1.5 mmol. Purification bynormal phase silica gel chromatography (eluted with 9:1 CH₂Cl₂:2M NH₃ inMeOH) followed by conversion to the HCl salt, as described in Example 5using the acetyl chloride/EtOH method to generate HCl in situ, afforded0.136 g (40%) ofdmethyl(3-{4-[5-naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.97 9d, 2H, J=9 Hz), 7.82–7.91 (m, 3H), 7.56 (d, 1H, J=3 Hz), 7.50 (t,1H, J=8 Hz), 7.40 (T, 1H, J=8 Hz), 7.29 (dd, 1H, J=3, 9 Hz), 7.15 (d,2H, J=9 Hz), 5.59 (s, 2H), 4.17 (t, 2H, J=6 Hz), 3.21 (t, 2H, J=8 Hz),2.78 (s, 6H), 2.12–2.21 (m 2H). IR (KBr, cm⁻¹) 2947, 2555, 2503, 2406,1618, 1500, 1467, 1393, 1247, 1209, 1178, 1116, 1059, 1012, 957, 839,805, 749, 472. MS (ES⁺) m/e 404. Analytical HPLC:100%. Mp(°C.)=Decomposes at 186.

Example 214 Preparation ofDimethyl-(3-{4-{5-(3-phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

a) 4-hydroxybenzoic acid N-[2-(3-phenoxypropoxy)acetyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from (3-phenoxypropoxy)acetic acid(2.70 g, 12.8 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(3.18 g, 12.8 mmol) and 4-hydroxybenzoic hydrazide (1.95 g, 12.8 mmol).The resultant crystalline material that formed in the reaction mixturewas collected by filtration to afford 2.42 g (55%) of 4-hydroxybenzoicacid N-[2-(3-phenoxypropoxy)acetyl]hydrazide.

¹H NMR (DMSO-d6)

10.06 (bs, 2H), 9.73 (bs, 1H), 7.74 (d, 2H, J=9 Hz), 7.24–7.31 (m, 2H),6.89–6.95 (m, 3H), 6.81 (d, 2H, J=9 Hz), 4.08 (t, 2H, J=6 Hz), 4.02 (s,2H), 3.67 (t, 2H, J=6 Hz), 1.98–2.06 (m, 2H). IR (KBr, cm⁻¹) 3219, 1686,1630, 1609, 1498, 1443, 1279, 1242, 1173, 1134, 755. MS (ES⁻) m/e 343.Anal. Calcd for C₁₈H₂₀N₂O₅ C, 62.78; H, 5.85; N, 8.13. Found C, 62.68;H, 5.74; N, 8.01.

b) 4-[-5-(3-Phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from of 4-hydroxybenzoic acidN-[2-(3-phenoxypropoxy)acetyl]hydrazide (2.07 g, 6.0 mmol),triphenylphosphine (3.15 g, 12.0 mmol), triethylamine (2.19 g, 21.6mmol) and carbon tetrabromide (3.99 g, 12.0 mmol). Purification bychromatography on silica gel (eluted with 1:1 EtOAc:hexane) afforded1.65 g (85%) of4-[-5-(3-Phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol as a solid.

¹H NMR (DMSO-d6)

10.32 (bs, 1H), 7.80 (d, 2H, J=9 Hz), 7.21–7.28 (m, 2H), 6.88–6.96 (m,5H), 4.77 (s, 2H), 4.02 (t, 2H, J=6 Hz), 3.70 (t, 2H, J=6 Hz), 1.95–2.04(m, 2H). IR (Br, cm⁻¹) 3101, 2958, 2871, 1609, 1497, 1470, 1285, 1240,1172, 1087, 757, 737. MS (ES⁺) m/e 327, MS (ES⁻) m/e 325. Anal. Calcdfor C₁₈H₁₈N₂O₄ C, 66.25; H, 5.56; N, 8.58. Found C, 66.28; H, 5.48; N,8.54.

c)Dimethyl-(3-{4-{5-(3-phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-[-5-(3-Phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenol (1.42 g, 4.4mmol), cesium carbonate (2.84 g, 8.7 mmol), and3-chloro-N,N-dimethylpropylamine HCl (0.688 g, 4.4 mmol). Purificationby radial chromatography on silica gel (eluted with a linear gradient of2 to 5% 2M NH₃ in MeOH:CHCl₃) followed by conversion to the HCl salt, asdescribed in Example 5 using the acetyl chloride/EtOH method to generateHCl in situ, afforded 0.311 g (16%) ofdimethyl-(3-{4-{5-(3-phenoxypropoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.91 (d, 2H, J=9 Hz), 7.21–7.27 (m, 2H), 7.13 (d, 2H, J=9 Hz), 6.88–6.92(m, 3H), 4.79 (s, 2H), 4.17 (t, 2H, J=6 Hz), 4.03 (t, 2H, J=6 Hz), 3.72(t, 2H, J=6 Hz), 3.21 (t, 2H, J=8 Hz), 2.78 (s, 6H), 2.14–2.24 (m, 2H),1.96–2.04 (m, 2H). IR (KBr, cm⁻¹) 2474, 1617, 1602, 1499, 1472, 1257,1171, 1085, 1052, 751. MS (ES⁺) m/e 412. Mp(° C.)=132.

Example 215 Preparation ofDimethyl-[3-(4-{5-[2-(2-phenxoyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenoxy)propyl]amine

a) 4-Hydroxybenzoic acid N′-[3-(2-phenoxyethoxy)propionyl]hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 3-(2-phenoxyethoxy)propionicacid (6.35 g, 30.2 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(7.47 g, 30.2 mmol) and 4-hydroxybenzoic hydrazide (4.64 g, 30.2 mmol).Purification by chromatography on silica gel (eluted with a lineargradient of 2 to 5% 2M NH₃ in MeOH:CHCl₃) afforded 4.73 g (70%) of4-hydroxybenzoic acid N′-[3-(2-phenoxyethoxy)propionyl]hydrazide as afoam.

¹H NMR (DMSO-d6)

10.06 (bs, 2H), 9.82 (bs, 1H), 7.73 (d, 2H, J=9 Hz), 7.23–7.31 (m, 2H),6.87–6.96 (m, 3H), 6.80 (d, 2H, J=8 Hz), 4.07 (t, 2H, J=5 Hz), 3.64–3.75(m, 4H), 2.41–2.54 (m, 2H). IR (CHCl₃, cm⁻¹) 3266, 3012, 2930, 2878,1688, 1646, 1609, 1497, 1456, 1279, 1245, 1225, 1173, 1122, 849. MS (ES)m/e 345, MS (ES⁻) m/e 343.

b) 4-{5-[2-(2-phenoxyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from of 4-hydroxybenzoic acidN′-[3-(2-phenoxyethoxy)propionyl]hydrazide (4.71 g, 13.7 mmol),triphenylphosphine (7.17 g, 27.4 mmol), triethylamine (4.98 g, 49.2mmol) and carbon tetrabromide (9.07 g, 27.4 mmol). Purification bychromatography on silica gel (eluted with 4:1 EtOAc:hexane) afforded4.40 g (99%) of4-{5-[2-(2-phenoxyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenol as an oil.Product co-eluted with triphenylphosphine.

¹H NM (DMSO-d6)

10.25 (bs, 1H), 7.78 (d, 2H, J=9 Hz), 7.21–7.27 (m, 2H), 6.88–6.94 (m,5H), 4.06–4.08 (m, 21), 3.91 (t, 2H, J=6 Hz), 3.76–3.79 (m, 2H), 3.18(t, 2H, J=6 Hz). IR (CHCl₃, cm⁻¹) 3006, 1732, 1615, 1600, 1499, 1438,1375, 1247, 1171, 1121, 1046. MS (ES⁺) m/e 327, MS (ES⁻) m/e 325.

c)Dimethyl-[3-(4-{5-[2-(2-phenxoyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenoxy)propyl]amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 21e, from4-{5-[2-(2-phenoxyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenol (2.02 g,6.1 mmol), cesium carbonate (3.98 g, 12.2 mmol), and3-chloro-N,N-dimethylpropylamine HCl (0.966 g, 6.1 mmol). Purificationby chromatography on silica gel (eluted with a linear gradient of 2 to10% 2M NH₃ in MeOH:CHCl₃) followed by conversion to the oxalate saltafforded 0.053 g (2%) ofdimethyl-[3-(4-{5-[2-(2-phenxoyethoxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenoxy)propyl]amineas the oxalate salt.

¹H NMR (DMSO-d6)

7.90 (d, 2H, J=9 Hz), 7.22–7.27 (m, 2H), 7.12 (d, 2H, J=9 Hz), 6.88–6.93(m, 3H), 4.14 (t, 2H, J=6 Hz), 4.05–4.09 (m, 2H), 3.92 (t, 2H, J=6 Hz),3.77–3.80 (m, 2H), 3.14–3.22 (m, 4H), 2.76 (s, 6H), 2.08–2.17 (m, 2H).IR (KBr, cm⁻¹) 1725, 1614, 1256, 1174, 1046, 840. MS (ES⁺) m/e 412, Mp(° C.)=116–118.

Example 216 Preparation of{3-[-4-(5-Biphenyl-2-yl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}dimethylamine

a) 4-Hydroxybenzoic acid N′-(biphenyl-2-caronyl)hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from 2-biphenylcarboxylic acid (2.42g, 12.2 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (3.02 g,12.2 mmol) and 4-hydroxybenzoic hydrazide (1.86 g, 12.2 mmol).Purification by chromatography on silica gel (eluted with a lineargradient of 2 to 10% 2M NH₃ in MeOH:CHCl₃) afforded 0.730 g (18%) of4-hydroxybenzoic acid N′-(biphenyl-2-caronyl)hydrazide as a solid.

¹H NMR (DMSO-d6) δ 10.26 (bs, 1H), 10.20 (bs, 1H), 10.08 (bs, 1H), 7.78(d, 2H, J=8 Hz), 7.30–7.62 (m, 9H), 6.81 (d, 2H, J=9 Hz). MS (ES⁺) m/e333, MS (ES⁻) m/e 331.

b) 4-(5-biphenyl-2-yl[1,3,4]oxadiazol-2-yl)phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from of 4-hydroxybenzoic acidN′-(biphenyl-2-caronyl)hydrazide (0.72 g, 2.2 mmol), triphenylphosphine(1.14 g, 4.3 mmol), triethylamine (0.44 g, 4.3 mmol) and carbontetrabromide (1.44 g, 4.3 mmol). Purification by radial chromatographyon silica gel (eluted with 4:1 EtOAc:hexane) afforded the crude productplus an impurity. The material was triterated in Et₂O then filtered. Theinsoluble material was collected to afford 0.288 g (42%) of4-(5-biphenyl-2-yl[1,3,4]oxadiazol-2-yl)phenol.

¹H NMR (DMSO-d6)

10.34 (bs, 1H), 8.05 (d, 1H, J=8 Hz), 7.69–7.74 (m, 1H), 7.59–7.65 (m,1H), 7.52–7.55 (m, 1H), 7.39–7.44 (m, 5H), 7.28–7.33 (m, 2H), 6.83 (d,2H, J=9 Hz). MS (ES⁺) m/e 315, MS (ES⁻) m/e 313

c){3-[-4-(5-Biphenyl-2-yl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-(5-biphenyl-2-yl[1,3,4]oxadiazol-2-yl)phenol (0.233 g, 0.7 mmol),sodium hydride (0.065 g, 1.6 mmol) and 3-chloro-N,N-dimehtylpropyl amineHCl (0.129 g, 8.2 mmol). Purification by radial chromatography on silicagel (eluted with 9:1 CHCl₃: 2M NH₃ in MeOH) followed by conversion tothe HCl salt, as described in Example 5 using the acetyl chloride/EtOHmethod to generate HCl in sit. Crystallization from MeOH:Et₂O afforded0.058 g (18%) of{3-[-4-(5-Biphenyl-2-yl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}dimethylamineas the hydrochloride salt.

¹H NMR (DMSO-d6)

10.21 (bs, 1H), 8.06–8.09 (m, 1H), 7.70–7.75 (m, 1H), 7.60–7.66 (m, 1H),7.51–7.57 (m, 3H), 7.40–7.44 (m, 3H), 7.29–7.33 (m, 2H), 7.05 (d, 2H,J=9 Hz), 4.13 (t, 2H, J=6 Hz), 3.19 (t, 2H, 8 Hz), 2.76 (s, 6H),2.09–2.17 (m, 2H). IR (KBr, cm⁻¹) 1612, 1498, 1477, 1254, 1178, 1045,836, 744. MS (ES⁺) m/e 400. Analytical HPLC:100%. Mp=(° C.)=177.

Example 217 Preparation of{3-[-4-(5-Biphenyl-3-yl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}dimethylamine

a) 4-Hydroxybenzoic acid N′-(biphenyl-3-caronyl)hydrazide

To a suspension of biphenyl-3-carboxylic acid (1.00 g, 5.0 mmol) in 25ml CH₂Cl₂ at room temperature was added oxalyl chloride (1.92 g, 15.1mmol) followed by three drops of DMF. The reaction was stirred at roomtemperature for 1.8 hours then heated at 40 C for four hours. Thereaction was then concentrated to an oil. This material was taken upinto 41 ml CH₃CN treated with triethylamine (0.510 g, 5.0 mmol),4-hydroxybenzoic hydrazide (0.786 g, 5.0 mmol) and dimethylaminepyridine (0.062 g, 0.5 mmol). The reaction mixture was heated at 60 Cfor two days then overnight at room temperature. The suspension wasconcentrated to a solid. The solid was treated with EtOAc and 5N HCl.The resultant suspension was filtered. The phases from the filtrate wereseparated. The organic phase was washed with 5N HCl, brine, dried overNa₂SO₄, filtered, concentrated to a semi-solid material. Triteration inCHCl₃ followed by filtration afforded the title compound along with animpurity. This material was taken on to the next step.

MS (ES⁺) m/e 333, MS (ES⁻) m/e 331.

b) 4-(5-biphenyl-3-yl[1,3,4]oxadiazol-2-yl)phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from of 4-Hydroxybenzoic acidN′-(biphenyl-3-caronyl)hydrazide (0.604 g, 1.8 mmol), triphenylphosphine(0.953 g, 3.6 mmol), triethylamine (0.368 g, 3.6 mmol) and carbontetrabromide (1.205 g, 3.6 mmol). Purification by radial chromatographyon silica gel (eluted with EtOAc) afforded 0.379 g (66%) of4-(5-biphenyl-3-yl[1,3,4]oxadiazol-2-yl)phenol.

¹H NMR (DMSO-d6)

10.34 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H, J=8 Hz), 8.01 (d, 2H, J=8 Hz),7.93 (d, 1H, J=8 Hz), 7.69–7.80 (m, 3H), 7.43–7.56 (m, 3H), 6.98 (d, 2H,J=9 Hz). IR (KBr, cm⁻¹) 1735, 1612, 1594, 1495, 1439, 1283, 1240, 1203,1169, 742, 719, 695. MS (ES⁺) m/e 315, MS (ES⁻) m/e 313.

c){3-[-4-(5-Biphenyl-2-yl-[1,3,4]oxadiazol-3-yl)phenoxy]propyl}dimethylamine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19e, from4-(5-biphenyl-3-yl[1,3,4]oxadiazol-2-yl)phenol (0.0.362 g, 1.2 mmol),sodium hydride (0.101 g, 2.5 mmol) and 3-chloro-N,N-dimehtylpropyl amineHCl (0.200 g, 1.3 mmol). Purification by radial chromatography on silicagel (eluted with 9:1 CHCl₃: 2M NH₃ in MeOH) followed by crystallizationfrom MeOH:Et₂O afforded 0.083 g (18%) of{3-[-4-(5-Biphenyl-2-yl-[1,3,4]oxadiazol-3-yl)phenoxy]propyl}dimethylamine.

¹H NMR (DMSO-d6)

8.35 (s, 1H), 8.09–8.13 (m, 3H), 7.93 (d, 1H, J=8 Hz), 7.79 (d, 2H, J=8Hz), 7.72 (t, 1H, J=8 Hz), 7.52–7.57 (m, 2H), 7.43–7.48 (m, 1H), 7.16(d, 2H, J=9 Hz), 4.12 (t, 2H, J=6 Hz), 2.38 (t, 2H, J=7 Hz), 2.14 (s,6H), 1.84–1.93 (m, 2H). IR (KBr, cm⁻¹) 2755, 1611, 1497, 1257, 1176,830, 739, 716. MS (ES⁺) m/e 400. Analytical HPLC:100%. Mp(° C.)=111.

Example 218 Preparation ofDimethyl-[3-(4-{5-[2-(2-phenoxyethyl)cyclopropylmethyl]-[1,3,4]-oxadiazol-2-yl}phenoxy)propyl]amine

a) trans-(2-Methoxycarbonylmethylcyclopropyl)acetic acid methyl ester

To a suspension of zinc-copper couple (44.82 g (0.35 mol) in 32 ml Et2Oundergoing sonication was added a solution of trans-3-hexene-1,6-dioicacid methyl ester (29.93 g, 0.17 mol) and methyl iodide (65.18 g (0.24mol) at a rate of 0.5 ml per ten minutes for the 90 minutes then 1.0 mlper ten minutes for the next 1.5 hours of the addition. At this pointthe addition was stopped and sonication continued for 1.5 hours. Afterthis the remaining material was added at a rate of 2.0 ml per tenminutes for the remainder of the addition. The reaction was sonicatedovernight. The reaction mixture solidified overnight. The mixture wastreated with 800 ml EtOAc then heated to 60 C to breakup the solidmaterial. This mixture was treated with filter agent then filtered. Thefiltrate was concentrated to an oil. The oil was dissolved into Et₂Othen washed with 100 ml 10% aqueous HCl, brine, dried over Na₂SO₄,filtered concentrated to an oil. Distillation at 115–120 C afforded 9.95g of a 1:1 mixture of trans-3-hexene-1,6-dioic acid methyl ester andtrans-(2-Methoxycarbonylmethylcyclopropyl)acetic acid methyl ester.

b) trans-(2-Methoxycarbonylmethylcyclopropyl)acetic acid

To a biphasic solution oftrans-(2-methoxycarbonylmethylcyclopropyl)acetic acid methyl ester(10.95 g, 58.8 mmol) in 200 ml aqueous potassium phosphate mono basic(2.76 g) was added porcine liver esterase (123 mg, approximately 5,060units). Next, 58.8 ml 1N LiOH solution was added in portions,maintaining pH between 7.0 and 7.5, over a two-hour period. The reactionwas stirred overnight at room temperature. Next, filter aid was addedand the reaction was filtered. The filtrate was extracted twice withEt₂O and the organic layer was discarded. The aqueous phase wasacidified with 1N HCl then extracted twice with Et₂O. The combinedorganic phases were dried over Na2SO4, filtered, concentrated to afford6.65 g of a 3:2 ratio of trans-hex-3-enedioic acid monomethyl ester:trans-(2-methoxycarbonylmethylcyclopropyl)acetic acid.

¹H NMR of title compound (DMSO-d6)

3.57 (s, 3H), 2.01–2.33 (m, 4H), 0.76–0.82 (m, 2H), 0.32–0.38 (m, 2H).MS (ES⁻) m/e 171.

c) trans-[2-(2-hydroxyethyl)cyclopropyl]acetic acid methyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 22a, from 3:2 ratio oftrans-hex-3-enedioic acid monomethyl ester:trans-(2-methoxycarbonylmethylcyclopropyl)acetic acid (8.49 g) to afford1.47 g mixture of 6-hydroxy-trans-hex-3-enoic acid methyl ester andtrans-[2-(2-hydroxyethyl)cyclopropyl]acetic acid methyl ester.

d) trans-[2-(2-phenoxyethyl)cyclopropyl]acetic acid methyl ester

To a mixture of trans-6-hydroxy-hex-3-enoic acid methyl ester andtrans-[2-(2-hydroxyethyl)cyclopropyl]acetic acid methyl ester (1.47 g),phenol (0.962 g, 10.2 mmol) and triphenylphosphine (2.68 g, 10.2 mmol)in 28 ml THF at 0 C was added dropwise diisopropylazodicarboxlate (2.07g, 10.2 mmol). The reaction was stirred overnight at room temperature.The mixture was concentrated to an oil. The oil was diluted with 50 mlEtOAc then washed twice with 1N NaOH, once with brine, dried overNa2SO4, filtered, concentrated to an oil. Purification by chromatographyon silica gel (eluted with 25%

EtOAc:hexane) followed by a second purification using chromasil (elutedwith linear gradient of 30 to 60% CH₂Cl₂:hexane) afforded a 3:2 ratio oftrans-[2-(2-phenoxyethyl)cyclopropyl]acetic acid methyl ester and6-phenoxy-trans-hex-3-enoic acid methyl ester.

The mixture of trans-[2-(2-phenoxyethyl)cyclopropyl]acetic acid methylester and 6-phenoxy-trans-hex-3-enoic acid methyl ester (0.954 g) in 3ml MeOH at −78 C was treated with ozone until a blue haze persisted inthe reaction mixture. Nitrogen was then bubbled through the reactionmixture. Next, dimethyl sulfide (0.354 g, 5.7 mmol) was added andstirring continued until the cooling bath warmed to room temperature,approximately 2.5 hours. The solution was then concentrated to an oil.

The oil was dissolved into 25 ml acetone then Jones Reagent (2.5 ml, 8.2mmol) was added. After stirring at room temperature for five minutes thereaction was quenched with aqueous sodium thiosulfate was added. Theproduct was extracted with Et₂O (2×50 ml), organic phases combined,washed with saturated aqueous sodium bicarbonate (2×50 ml), brine, driedover Na₂SO₄, filtered, concentrated to an oil. Purification by radialchromatography on silica gel (eluted with 3:1 hexane:Et₂O) afforded0.395 g of trans-[2-(2-phenoxyethyl)cyclopropyl]acetic acid methyl esteras an oil.

¹H NMR (DMSO-d6)

7.24–7.30 (m, 2H), 6.88–6.93 (m, 3H), 3.99 (t, 2H, J=7 Hz), 3.52 (s,31), 2.15–2.35 (m, 2H), 1.54–1.73 (m, 2H), 0.66–0.84 (m, 2H), 0.31–0.41(m, 2H). MS (TOF) m/e 170.

e) trans-[2-(2-phenxoyethyl)cyclopropyl]acetic acid

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 1a, fromtrans[2-(2-phenoxyethyl)cyclopropyl]acetic acid methyl ester (0.371 g,1.6 mmol) and lithium hydroxide (0.114 g, 4.8 mmol) afforded 0.291 g oftrans-[2-(2-phenxoyethyl)cyclopropyl]acetic acid as an oil thatcrystallizes out.

¹H NMR (DMSO-d6)

7.24–7.30 (m, 2H), 6.88–6.95 (m, 3H), 4.01 (t, 2H, J=7 Hz), 2.06–2.24(m, 2H), 1.59–1.68 (m, 2H), 0.75–0.84 (m, 1H), 0.63–0.71 (m, 1H),0.29–0.39 (m, 2H). IR (KBr, cm⁻¹) 3038, 2999, 2947, 2928, 1713, 1601,1499, 1254, 1244, 1225, 1210, 1038, 754, 692. MS (ES⁻) m/e 219. Anal.Calcd for C₁₃H₁₆O₃ C, 70.89; H, 7.32. Found C, 70.75; H, 7.50.

f) 4-(3-Dimethylaminopropoxy)benzoic acidN′-trans-{2-[2-(2-phenoxyethyl)cyclopropyl]acetyl}hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19c, from oftrans-[2-(2-phenxoyethyl)cyclopropyl]acetic acid (0.274 g, 1.2 mmol),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.308 g, 1.2 mmol) and4-hydroxybenzoic hydrazide (0.295 g, 1.2 mmol). Purification by radialchromatography on silica gel (eluted with 95:5 CHCl₃:2M NH₃ inMeOH:CHCl₃) afforded 0.055 g (10%) of 4-(3-dimethylaminopropoxy)benzoicacid N′-trans-{2-[2-(2-phenoxyethyl)cyclopropyl]acetyl}hydrazide.

g)Dimethyl-[3-(4-{5-[2-(2-phenoxyethyl)cyclopropylmethyl]-[1,3,4]-oxadiazol-2-yl}phenoxy)propyl]amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 19d, from4-(3-dimethylaminopropoxy)benzoic acidN′-trans-{2-[2-(2-phenoxyethyl)cyclopropyl]acetyl}hydrazide (0.055 g,0.13 mmol), triphenylphosphine (0.066 g, 0.25 mmol), triethylamine(0.025 g, 0.25 mmol) and carbon tetrabromide (0.083 g, 0.25 mmol).Purification by radial chromatography on silica gel (eluted with 9:1CHCl₃:2M NH₃ in MeOH) followed by formation of the oxalate salt afforded0.061 (95%) g of dimethyl-trans-[3-(4-{5-[2-(2-phenoxyethyl)cyclo propylmethyl]-[1,3,4]-oxadiazol-2-yl}phenoxy)propyl]amine as the oxalate salt.

¹H NMR (DMSO-d6) δ 7.90 (d, 2H, J=9 Hz), 7.18–7.23 (m, 21), 7.10 (d, 2H,J=9 Hz), 6.81–6.90 (m, 31), 4.13 (t, 2H, J=6 Hz), 3.94–3.99 (m, 2H),3.13–3.18 (m, 2H), 2.94–3.01 (m, 1H), 2.73–2.81 (m, 7H), 2.09–2.14 (m,2H), 1.73–1.79 (m, 1H), 1.51–1.61 (m, 1H), 0.96–1.02 (m, 1H), 0.83–0.93(m, 1H), 0.45–0.57 (m, 2H). IR (KBr, cm⁻¹) 3042, 2937, 2869, 1720, 1615,1501, 1472, 1257, 1176, 476. MS (ES⁺) m/e 421. Anal. Calcd forC₂₅H₃₁N₃O₃ C₂H₂O₄ C, 63.39; H, 6.50; N, 8.21. Found C, 63.35; H, 6.55;N, 8.22. Mp(° C.)=141.

Example 219 Preparation of1-{3-[4-(5-Phenylsulfanylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine

a) Acetic acid 5-(4-hydroxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl ester

To 4-hydroxybenzoic hydrazide (4.39 g, 28.9 mmole) in 145 ml CH₃CN and35 ml THF at room temperature was added a solution of acetoxyacetylchloride (3.59 g, 26.3 mmol) in 30 ml CH₃CN over a five-minute period.The suspension was then stirred at room temperature for two hours. Tothis suspension was added triethylamine (6.38 g, 63.0 mmol),triphenylphosphine (8.26 g, 31.5 mmol) and carbon tetrabromide (10.45 g,31.5 mmol). The resultant red solution was stirred 16 hours at roomtemperature. The mixture was concentrated to an oil. The oil was dilutedwith 250 ml EtOAc then washed with 0.1 N HCl (2×250 ml), brine (250 ml),dried over Na₂SO₄, filtered, concentrated to afford a red oil.Purification from chromatography on silica gel (eluted with EtOAc)afforded a solid. Crystallization from Et₂O afforded 1.99 g of the titlecompound. The filtrate from the crystallization was concentrated toafford an additional 1.06 g of the title compound. A total of 3.05 g(50%) of acetic acid 5-(4-hydroxyphenyl)-[1,3,4]oxadiazol-2-ylmethylester was isolated.

¹H NMR (DMSO-d6)

10.33 (bs, 1H), 7.81 (d, 2H, J=9 Hz), 6.93 (d, 2H, J=9 Hz), 5.33 (s,2H), 2.12 (s, 3H). IR (KBr, cm⁻¹) 3147, 1757, 1606, 1590, 1512, 1443,1411, 1369, 1285, 1211, 1181, 1094, 1066, 968, 846, 741, 626, 521. MS(ES⁺) m/e 235, MS (ES⁻) m/e 233.

b) 5-[4-(3-Piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol

To acetic acid 5-(4-hydroxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl ester(4.96 g, 21.2 mmol), triphenyl phosphine (8.33 g, 31.8 mmol) and3-N-piperidino-1-propanol (4.79 g, 31.8 mmol) in 65 ml THF at 0 C wasadded diisopropylazodicarboxylate 6.42 g, 31.8 mmol) over a ten minuteperiod. The resultant orange solution was stirred at room temperaturefor six hours. Next, 50 ml 1N NaOH was added and the reaction wasstirred thirty minutes at room temperature. The reaction mixture wasthen extracted with EtOAc (2×100 ml). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to anoil. Purification by chromatography on silica gel (eluted with a stepgradient of 5 L CH₂Cl₂, 5 L 5% 2M NH₃ IN MeOH:CH₂Cl₂, 5 L 7.5% 2M NH₃ INMeOH:CH₂Cl₂) to afford an oil. Treatment of the oil with Et2O resultedin a suspension. The insoluble material was collected by filtration toafford 4.64 g (69%) of{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol.

¹H NMR (DMSO-d6)

7.89 (d, 2H, J=9 Hz), 7.10 (d, 2H, J=9 Hz), 5.91 (t, 1H, J=6 Hz), 4.67(d, 2H, J=6 Hz), 4.09 (t, 2H, J=6 Hz), 2.25–2.42 (m, 6H), 1.85–1.93 (m,2H), 1.44–1.54 (m, 4H), 1.32–1.41 (m, 2H). IR (KBr, cm⁻¹) 3061, 2935,2811, 1618, 1499, 1464, 1430, 1311, 1260, 1176, 1126, 1053, 839, 780,738, 679, 528. MS (ES⁺) m/e 318.

c)1-{3-[4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine

To{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-yl}methanol(0.159 g, 0.5 mmol) in 5.0 ml CH₂Cl₂ at room temperature was addedthionyl chloride (1.67 g, 14.03 mmol). The reaction was stirred at roomtemperature for 1.5 hours then concentrated to a solid. This materialwas dissolved into CH₂Cl₂:H₂O and 1N NaOH added until pH was greaterthan 12. The phases were separated, aqueous phase extracted with CH₂Cl₂.The organic phases were combined, washed with brine, dried over Na₂SO₄,filtered, concentrated to afford 0.146 g (87%) of1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidineas a crystalline solid.

¹H NMR (DMSO-d6)

7.90 (d, 2H), 7.13 (d, 2H), 5.09 (s, 2H), 3.08 (t, 2H), 2.26–2.40 (m,6H), 1.84–1.93 (m, 2H), 1.45–1.51 (m, 4H), 1.33–1.40 (m, 2H). MS (ES⁺)m/e 336.

d)1-{3-[4-(5-Phenylsulfanylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine

Method A: A suspension of1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.071 g, 0.21 mmol), cesium carbonate (0.076 g, 0.23 mmol) andbenzenethiol (0.026 g, 0.23 mmol) in 1.0 ml acetone was stirred at roomtemperature for 1.0 hour refluxed for 1.0 hour. After cooling to roomtemperature the suspension was filtered.

Method B: To benzenethiol (0.026 g, 0.23 mmol) in 1.0 ml THF was addedsodium hydride (0.009 g, 0.23 mmol) at room temperature. The mixture wasstirred five minutes then1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.071 g, 0.23 mmol) was added. The reaction mixture was stirred at roomtemperature for 1.0 hour then refluxed for 1.0 hour. After cooling toroom temperature the suspension was filtered.

The filtrates from Method A and Method B were combined, concentrated invacuo. Purification by radial chromatography (eluted with 5% 2M NH₃ inMeOH:CH₂Cl₂) followed by conversion to the HCl salt, as described inExample 5 using the acetyl chloride/EtOH method to generate HCl in situ,afforded 0.066 g (35%) of1-{3-[4-(5-Phenylsulfanylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidineas the hydrochloride salt.

¹HNMR (DMSO-d6)

10.10 (bs, 1H), 7.81 (d, 2H, J=9 Hz), 7.44–7.47 (m, 2H), 7.32–7.37 (m,2H), 7.24–7.28 (m, 1H), 7.12 (d, 2H, J=9 Hz), 4.57 (s, 2H), 4.20 (t, 2H,J=6 Hz), 3.43–3.46 (m, 2H), 3.13–3.20 (m, 2H), 2.81–2.92 (m, 2H),2.16–2.25 (m, 2H), 1.66–1.82 (m, 5H), 1.33–1.42 (m, 1H). IR (KBr, cm⁻¹)2940, 2621, 2503, 1615, 1499, 1440, 1393, 1309, 1250, 1178, 1054, 1015,976, 943, 840, 742, 688. MS (ES⁺) m/e 410. Anal. Calcd for C₂₃H₂₇N₃O₂SHCl C, 61.94; H, 6.33; N, 9.42. Found C, 61.62; H, 6.38; N, 9.28.Analytical HPLC: 100%. Mp(° C.)=152.

Example 220 Preparation of1-(3-{4-[5-(biphenyl-4-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

To a solution of biphenyl-4-thiol (0.153 g, 0.82 mmol) in 3.5 ml THF atroom temperature was added sodium hydride (0.033 g, 0.82 mmol). Thereaction mixture was stirred five minutes then1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) was added followed by 2 ml THF. The reaction washeated at 60 C for one hour. After cooling to room temperature thereaction was diluted with 50 ml H₂O and extracted with EtOAc (2×50 ml).The organic phases were washed with brine, dried over Na2SO4, filtered,concentrated in vacuo. Purification by radial chromatography (elutedwith 5% 2M NH₃ in MeOH:CH₂Cl₂) followed by conversion to the HCl salt,as described in Example 5 using the acetyl chloride/EtOH method togenerate HCl in situ, afforded 0.088 g (23%) of1-(3-{4-[5-(biphenyl-4-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdineas the hydrochloride salt.

¹H NMR (DMSO-d6) δ 107.84 (d, 2H, J=9 Hz),7.66 (d, 4H, J=8 Hz), 7.55 (d,2H, J=8 Hz), 7.44–7.49 (m, 2H), 7.35–7.39 (m, 1H), 7.10 (d, 2H, J=9 Hz),4.63 (s, 2H), 4.14 (t, 2H, J=6 Hz), 3.39–3.50 (m, 2H), 3.11–3.22 (m,2H), 2.81–2.92 (m, 2H), 2.11–2.22 (m, 2H), 1.61–1.85 (m, 5H), 1.31–1.42(m, 1H). IR (KBr, cm⁻¹) 3420, 3053, 3027, 2940, 2612, 2488, 1615, 1500,1479, 1300, 1254, 1174, 1085, 1005, 948, 835, 761, 698. MS (ES⁺) m/e486. Mp(° C.)=142.

Example 221 Preparation of1-(3-{4-[5-(Naphthalen-1-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 1-naphthalenethiol (0.131 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.162 g (44%) of1-(3-{4-[5-(naphthalen-1-yl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdineas the hydrochloride salt.

¹H NMR (DMSO-d6)

8.24–8.29 (m, 1H), 7.91–8.00 (m, 2H), 7.79 (d, 1H, J=7 Hz), 7.70 (d, 2H,J=9 Hz), 7.48–7.58 (m, 3H), 7.08 (d, 2H, J=9 Hz), 4.58 (s, 2H), 4.15 9t, 2H, J=6 Hz), 3.37–3.45 (m, 2H), 3.13–3.22 (m, 2H), 3.81–3.94 (m, 2H),2.11–2.34 (m, 2H), 1.65–1.84 (m, 5H), 1.31–1.43 (m, 1H). IR (KBr, cm⁻¹)3050, 2947, 2462, 2403, 1615, 1591, 1497, 1465, 1427, 1307, 1252, 1171,1066, 950, 844, 793, 767. MS (ES⁺) m/e 460. Anal. Calcd for C₂₇H₂₉N₃O₂SHCl C, 65.37; H, 6.10; N, 8.47. Found C, 65.13; H, 6.09; N, 8.22. Mp(°C.)=195.

Example 222 Preparation of2-{5-[4-(3-Piperidin-1-yl-propoxy)phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl}benzothiazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercaptobenzothiazole (0.137g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.170 g (49°/O) of2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}benzothiazoleas the hydrochloride salt.

¹H NMR (DMSO-d6) δ 8.05 (d, 1H, J=8 Hz), 7.85–7.90 (m, 3H), 7.45–7.51(m, 1H), 7.38–7.44 (m, 1H), 7.12 (d, 2H, J=7 Hz), 5.01 (s, 2H), 4.15 (t,2H, J=6 Hz), 3.39–3.50 (m, 2H), 3.13–3.22 (m, 2H), 2.81–2.93 (m, 2H),2.12–2.23 (m, 2H), 1.64–1.84 (m, 5H), 1.31–1.41 (m, 1H). IR (KBr, cm⁻¹)3431, 2948, 2617, 2486, 1612, 1499, 1457, 1426, 1306, 1253, 1175, 1049,1004, 942, 835, 753, 724. MS (ES⁺) m/e 467. Mp(° C.)=144.

Example 223 Preparation of2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercaptobenzimidazole (0.246g, 1.64 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.500 g, 1.49 mmol) and sodium hydride (0.066 g, 1.64 mmol) to afford0.364 g (54%) of2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole.

¹H NMR (DMSO-d6)

7.75 (d, 2H), 7.33–7.54 (m, 2H), 7.10–7.15 (m, 2H), 7.04 (d, 2H), 4.85(s, 2H), 4.05 (t, 2H), 2.26–2.39 (m, 6H), 1.83–1.91 (m, 2H), 1.45–1.50(m, 4H), 1.33–1.40 (m, 2H). IR (KBr, cm⁻¹) 3068, 2935, 2878, 2803, 1619,1500, 1430, 1401, 1352, 1301, 1252, 1179, 1008, 841, 741, 523. MS (ES⁺)m/e 450. Anal. Calcd for C₂₄H₂₇N₅O₂S C, 64.12; H, 6.05; N, 15.58. FoundC, 64.07; H, 6.06; N, 15.41. Mp(° C.)=193.

Example 224 Preparation of1-(3-{4-[5-(1H-Imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercaptoimidazole (0.082 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.128 g (43%) of1-(3-{4-[5-(1H-imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine.

¹H NMR (DMSO-d6)

7.79 (d, 2H, J=9 Hz), 7.25 (s, 1H), 7.08 (d, 2H, J=9 Hz), 4.40 (s, 2H),4.05 (t, 2H, J=6 Hz), 2.24–2.39 (m, 6H), 1.77–1.92 (m, 2H), 1.39–1.52(m, 4H), 1.30–1.39 (m, 2H). IR (KBr, cm⁻¹) 2992, 2937, 2765, 1616, 1500,1428, 1329, 1303, 1250, 1179, 1098, 1007, 960, 846, 756, 657. MS (ES⁺)m/e 400. Anal. Calcd for C₂₀H₂₅N₅O₂S C, 60.13; H, 6.31; N, 17.53. FoundC, 59.84; H, 6.19; N, 17.27. Mp(° C.)=132.

Example 225 Preparation of1-(3-{4-[5-([1,3,4]thiadiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercapto-1,3,4-thiadiazole(0.097 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.154 g (46%) of1-(3-{4-[5-([1,3,4]thiadiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine220 as the hydrochloride salt.

¹H NMR (DMSO-d6)

9.56 (s, 1H), 7.86 (d, 2H, J=9 Hz), 7.12 (d, 2H, J=9 Hz), 4.92 (s, 2H),4.15 (t, 2H, J=6 Hz), 3.42–3.48 (m, 2H), 3.14–3.20 (m, 2H), 2.81–2.89(m, 2H), 2.15–2.22 (m, 2H), 1.66–1.82 (m, 5H), 1.33–1.39 (m, 1H). IR(KBr, cm⁻¹) 2945, 2634, 2508, 1615, 1498, 1429, 1367, 1310, 1254, 1175,1060, 974, 944, 840, 739. MS (ES⁺) m/e 418, MS (ES⁻) m/e 416. AnalyticalHPLC: 100%. Anal. Calcd for C₁₉H₂₃N₅O₂S₂ HCl C, 50.27; H, 5.33; N,15.43. Found C, 50.09; H, 5.31; N, 15.17. Mp(° C.)=164.

Example 226 Preparation of1-(3-{4-[5-(thiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercaptothiazole (0.096 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.154 g (46%) of1-(3-{4-[5-(thiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.85 (d, 2H, J=9 Hz), 7.78 (s, 1H), 7.74 (s, 1H), 7.12 (d, 2H, J=9 Hz),4.79 (s, 2H), 4.15 (t, 2H, J=6 Hz), 3.41–3.46 (m, 2H), 3.13–3.20 (m,2H), 2.82–2.90 (m, 2H), 2.12–2.20 (m, 2H), 1.75–1.81 (m, 2H), 1.63–1.72(m, 2H), 1.32–1.39 (m, 1H). IR (KBr, cm⁻¹) 3074, 2963, 2940, 2918, 2618,2499, 1614, 1498, 1472, 1430, 1310, 1251, 1180, 1034, 942, 838, 738,662. MS (ES⁺) m/e 417, MS (ES⁻) m/e 415. Analytical HPLC: 100%. Anal.Calcd for C₂₀H₂₄N₄O₂S₂ HCl C, 53.03; H, 5.56; N, 12.37. Found C, 52.92;H, 5.54; N, 12.17. Mp(° C.)=174–176.

Example 227 Preparation of1-(3-{4-(5-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from2-mercapto-5-methyl-1,3,4-thiadiazole (0.108 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.163 g (32%) of1-(3-{4-[5-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine.

¹H NMR (DMSO-d6)

7.83 (d, 2H, J=9 Hz), 7.11 (d, 2H, J=9 Hz), 4.85 (s, 2H), 4.08 (t, 2H,J=7 Hz), 2.69 (s, 3H), 2.25–2.39 (m, 6H), 1.81–1.89 (m, 2H), 1.43–1.51(m, 4H), 1.32–1.39 (m, 2H).IR (KBr, cm⁻¹) 2933, 2807, 1608, 1499, 1421,1387, 1307, 1262, 1176, 1125, 1068, 1018, 954, 854, 741. MS (ES⁺) m/e432, MS (ES⁻) m/e 430. Analytical HPLC: 100%. Anal. Calcd forC₂₀H₂₅N₅O₂S₂ C, 55.66; H, 5.84; N, 16.23. Found C, 55.75; H, 5.86; N,16.08. Mp(° C.)=89.

Example 228 Preparation of1-(3-{4-[5-(4-Phenylthiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercapto-4-phenylthiazole(0.158 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.080 g (39%) of1-(3-{4-[5-(4-phenylthiazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdineas the hydrochloride salt.

¹H NMR (DMSO-d6)

8.08 (s, 1H), 7.86–7.88 (m, 4H), 7.29–7.39 (m, 3H), 7.10 (d, 2H, J=9Hz), 4.86 (s, 2H), 4.14 (t, 2H, J=6 Hz), 3.41–3.47 (m, 2H), 3.13–3.20(m, 2H), 2.81–2.92 (m, 2H), 2.14–2.22 (m, 2H), 1.65–1.82 (m, 5H),1.33–1.41 (m, 1H). IR (KBr, cm⁻¹) 2947, 2616, 2468, 2412, 1614, 1498,1476, 1424, 1306, 1252, 1174, 1034, 839, 729. MS (ES⁺) m/e 493, MS (ES⁻)m/e 491. Analytical HPLC: 100%. Mp(° C.)=141.

Example 229 Preparation of1-(3-{4-[5-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercapto-1-methylimidazole(0.093 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.228 g (37%) of1-(3-{4-[5-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperdine as the hydrochloride salt.

¹H NMR (DMSO-d6)

7.84 (d, 2H, J=9 Hz), 7.57 (s, 1H), 7.36 (s, 1H), 7.13 (d, 2H, J=9 Hz),4.58 (s, 2H), 4.15 (t, 2H, J=6 Hz), 3.67 (s, 3H), 3.40–3.47 (m, 2H),3.11–3.47 (m, 2H), 2.82–2.92 (m, 2H), 2.14–2.23 (m, 2H), 1.63–1.82 (m,5H), 1.31–1.42 (m, 1H). IR (KBr, cm⁻¹) 3418, 2946, 2615, 2488, 1899,1615, 1570, 1499, 1471, 1428, 1299, 1251, 1178, 1056, 943, 837, 736. MS(ES⁺) m/e 414. Mp(° C.)=173.

Example 230 Preparation of2-{5-[4-(3-Piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}benzooxazole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-mercaptobenzoxazole (0.099 g,0.66 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.200 g, 0.60 mmol) and sodium hydride (0.026 g, 0.66 mmol) to afford0.097 g (27%) of2-{5-[4-(3-Piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}benzooxazole

¹H NMR (DMSO-d6)

7.81 (d, 2H, J=9 Hz), 7.64–7.68 (m, 2H), 7.32–7.37 (m, 2H), 7.08 (d, 2H,J=9 Hz), 4.95 (s, 2H), 4.06 (t, 2H, J=6 Hz), 2.27–2.38 (m, 6H),1.82–1.89 (m, 2H), 1.44–1.49 (m, 4H), 1.33–1.38 (m, 2H). IR (KBr, cm⁻¹)2930, 2846, 2770, 1613, 1590, 1504, 1453, 1312, 1259, 1180, 1134, 1096,1014, 955, 846, 807, 741, 702, 657. MS (ES⁺) m/e 451. Anal. Calcd forC₂₄H₂₆N₄O₃S C, 63.98; H, 5.82; N, 12.43. Found C, 63.95; H, 5.79; N,12.35. Mp(° C.)=108.

Example 231 Preparation of1-Methyl-2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole

Method A: To a solution of2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole(0.066 g, 0.15 mmol) in 3 ml DMF at room temperature was added potassiumcarbonate (0.022 g, 0.15 mmol), tertabutylammonium bromide (0.005 g,0.02 mmol) and dimethyl sulfate (0.019 g, 0.15 mmol). The reaction wasstirred at room temperature for 5 days.

Method B: To a suspension of2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole(0.052 g, 0.12 mmol) in 3 ml acetone was added potassium carbonate(0.018 g, 0.135 mmol), tertabutylammonium bromide (0.004 g, 0.01 mmol)and dimethyl sulfate (0.015 g, 0.12 mmol). The reaction was stirred atroom temperature for 6 days.

The reactions were combined and diluted with 25 ml H₂O then extractedwith EtOAc (2×25 ml). The organic phases were combined, washed withbrine, dried over Na2SO4, filtered, concentrated to an oil. Purificationby radial chromatography on silica gel (eluted with 5% 2M NH₃ inMeOH:CH₂Cl₂) followed by conversion to the di-HCl salt as described inExample 5 using the acetyl chloride/EtOH method to generate HCl in situafforded 0.016 g (14%) of1-methyl-2-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-benzimidazole.

¹H NMR (DMSO-d6)

7.83 (d, 2H), 7.51–7.55 (m, 2H), 7.14–7.25 (m, 2H), 7.08 (d, 2H), 4.90(s, 2H), 4.14 (t, 2H), 3.73 (s, 3H), 3.41–3.49 (m, 2H), 3.14–3.21 (m,2H), 2.81–2.93 (m, 2H), 2.14–2.23 (m, 2H), 1.65–1.83 (m, 5H), 1.31–1.45(m, 1H). MS (ES⁺) m/e 464. Mp(° C.)=194.

Example 232 Preparation ofDimethyl-{3-[4-(5-phenethylsulfanylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 193c from thiobenzoic acidS-(2-{N′-[4-(3-dimethylamino propoxy)benzoyl]hydrazino}-2-oxoethyl)ester(0.205 g, 0.5 mmol), (2-bromoethyl) benzene (0.095 g, 0.5 mmol) andlithium hydroxide (0.025 g, 1.0 mmol) to afford 0.139 g (62%) ofdimethyl-{3-[4-(5-phenethylsulfanylmethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}amineas the hydrochloride salt.

¹H NMR (DMSO-d6)

790 (d, 2H, J=9 Hz), 7.05–7.23 (m, 7H), 4.15 (t, 2H, J=6 Hz), 4.10 (s,2H), 3.16–3.22 (m, 2H), 2.86 (s, 4H), 2.79 (s, 6H), 2.09–2.17 (m, 2H).MS (ES⁺) m/e 398. Analytical HPLC: 100%. Anal. Calcd for C₂₂H₂₇N₃O₂S HClC, 60.89; H, 6.50; N, 9.68. Found C, 60.64; H, 6.47; N, 9.67. Mp(°C.)=Decomposes at 173.

Example 233 Preparation of1-(3-{4-[5-Phenyl-1H-tetrazol-5-yl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 28 from 1-phenyl-1H-tetrazole (0.146 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.244 g (64%) of1-(3-{4-[5-Phenyl-1H-tetrazol-5-yl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹HNMR (DMSO-d6)

7.85 (d, 2H, J=9 Hz), 7.63 (s, 5H), 4.88 (s, 2H), 4.15 (t, 2H, J=6 Hz),3.41–3.48 (m, 2H), 3.12–3.21 (m, 2H), 2.81–2.92 (m, 2H), 2.12–2.22 (m,2H), 1.63–1.83 (m, 5H), 1.31–1.41 (m, 1H). IR (KBr, cm⁻¹) 2946, 2621,2499, 2407, 1615, 1499, 1390, 1309, 1252, 1390, 1309, 1252, 1173, 1066,1015, 838, 767, 738, 696. MS (ES⁺) m/e 451. Analytical HPLC: 100%. Anal.Calcd for C₂₄H₂₇N₇O₂S HCl C, 56.08; H, 5.49; N, 19.07. Found C, 56.02;H, 5.509; N, 18.86. Mp(° C.)=Decomposes at 182.

Example 234 Preparation of1-(3-{4-[5-(5-Phenyl-[1,3,4]oxadiazol-2-yl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from5-phenyl-1,3,4-oxadiazole-2-thiol (0.146 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.259 g (73%) of1-(3-{4-[5-(5-Phenyl-[1,3,4]oxadiazol-2-yl-sulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine.

¹H NMR (DMSO-d6)

7.94 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=9 Hz), 7.54–7.64 (m, 3H), 7.07 (d,2H, J=9 Hz), 4.89 (s, 2H), 4.07 (t, 2H, J=6 Hz), 2.21–2.42 (m, 6H),1.80–1.91 (m, 2H), 1.41–1.51 (m, 4H), 1.29–1.40 (m, 2H). IR (KBr, cm⁻¹)3067, 2929, 2851, 2752, 1609, 1570, 1480, 1416, 1303, 1253, 1179, 1125,1065, 1021, 988, 955, 848, 741, 704. MS (ES⁺) m/e 478, MS (ES⁻) m/e 476.Anal. Calcd for C₂₅H₂₇N₅O₃S C, 62.87; H, 5.70; N, 14.66. Found C, 62.75;H, 5.63; N, 14.53. Mp(° C.)=118.

Example 235 Preparation of1-(3-{4-[5-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from4-methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol (0.157 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl)piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.132 g (34%) of1-(3-{4-[5-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.84 9d, 2H, J=9 Hz), 7.65–7.70 (m, 2H), 7.53–7.57 (m, 3H), 7.10 (d, 2H,J=9 Hz), 4.68 (s, 2H), 4.14 (t, 2H, J=6 Hz), 3.40–3.48 (m, 2H),3.12–3.20 (m, 2H), 2.81–2.91 (m, 2H), 2.15–2.23 (m, 2H), 1.65–1.81 (m,5H), 1.32–1.40 (m, 1H). IR (KBr, cm⁻¹) 3420, 2944, 2623, 2514, 1615,1501, 1472, 1398, 1252, 1179, 1068, 942, 842, 777, 705. MS (ES⁻) m/e489. Analytical HPLC: 100%. Mp(° C.)=Decomposes at 174.

Example 236 Preparation of2-(4-Methyl-5-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-4H-[1,2,4]triazol-3-yl)pyridine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from4-methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol (0.157 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.161 g (41%) of2-(4-Methyl-5-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-4H-[1,2,4]triazol-3-yl)pyridineas the dihydrochloride salt.

¹H NMR (DMSO-d6)

8.70 (d, 1H, J=4 Hz), 8.11 (d, 1H, J=8 Hz), 7.97–8.02 (m, 1H), 7.83 (d,2H, J=9 Hz), 7.51–7.54 (m, 1H), 7.07 (d, 2H, J=9 Hz), 4.69 (s, 2H), 4.15(t, 2H, J=6 Hz), 3.42–3.49 (m, 2H), 3.14–3.21 (m, 2H), 2.82–2.91 (m,2H), 2.13–2.20 (m, 2H), 1.76–1.84 (m, 2H), 1.65–1.73 (m, 3H), 1.34–1.40(m, 1H). IR (KBr, cm⁻¹) 3420, 2948, 2619, 2498, 1829, 1613, 1569, 1500,1469, 1307, 1255, 1176, 1084, 945, 837, 795, 738, 709. MS (ES⁺) m/e 491.Analytical HPLC: 100%. Mp(° C.)=112.

Example 237 Preparation of3-(4-Methyl-5-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-4H-[1,2,4]triazol-3-yl)pyridine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol (0.157 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.138 g (38%) of3-(4-Methyl-5-{5-[4-(3-piperidin-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-4H-[1,2,4]triazol-3-yl)pyridine.

¹H NMR (DMSO-d6)

8.87 (s, 1H), 8.72 (d, 1H, J=5 Hz), 7.81 (d, 1H, J=9 Hz), 7.57–7.60 (m,1H), 7.08 (d, 2H, J=9 Hz), 4.70 (s, 2H), 4.07 (t, 2H, J=6 Hz), 2.26–2.39(m, 6H), 1.82–1.89 (m, 2H), 1.42–1.52 (m, 4H), 1.30–1.40 (m, 2H). IR(KBr, cm⁻¹) 2932, 2761, 1614, 1569, 1500 1422, 1367, 1301, 1255, 1176,1158, 1093, 1028, 856, 818, 712. MS (ES⁺) m/e 492, MS (ES⁻) m/e 490.Analytical HPLC: 100%. Anal. Calcd for C₂₅H₂₉N₇O₂S C, 61.08; H, 5.95; N,19.94. Found C, 60.93; H, 5.94; N, 19.71. Mp(° C.)=118.

Example 238 Preparation of1-(3-{4-[5-Phenyl-1H-imidazol-2-ylsulfanylmethyl-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 1-phenyl-1H-imidazole-2-thiol(0.144 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.295 g (77%) of1-(3-{4-[5-Phenyl-1H-imidazol-2-ylsulfanylmethyl-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine as the dihydrochloride salt.

¹H NMR (DMSO-d6)

7.76–7.84 (m, 3H), 7.59 (s, 1H), 7.35–7.48 (m, 5H), 7.13 (d, 2H, J=9Hz), 4.56 (s, 2H), 4.16 (t, 2H, J=6 Hz), 3.41–3.48 (m, 2H), 3.13–3.20(m, 2H), 2.81–2.92 (m, 2H), 2.18–2.27 (m, 2H), 1.74–1.83 (m, 4H),1.66–1.73 (m, 1H), 1.33–1.43 (m, 1H). IR (KBr, cm⁻¹) 3415, 3162, 2944,2681, 2490, 1731, 1612, 1567, 1500, 1430, 1373, 1304, 1254, 1180, 1088,1008, 845, 758, 697. MS (ES⁺) m/e 476. Mp(° C.)=Decomposes at 177.

Example 239 Preparation of1-(3-{4-[5-(1-Naphthalen-1-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from1-naphthalene-1yl-1H-imidazole-2-thiol (0.185 g, 0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.358 g (86%) of1-(3-{4-[5-(1-Naphthalen-1-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the dihydrochloride salt.

¹H NMR (DMSO-d6)

8.10 (d, 1H, J=7 Hz), 8.03 (d, 1H, J=8 Hz), 7.75–7.80 (m, 3H), 7.48–7.59(m, 41), 7.34–7.39 (m, 1H), 7.13 (d, 2H, J=9 Hz), 7.05 (d, 1H, J=8 Hz),4.40–4.60 (m, 2H), 4.18 (t, 2H, J=6 Hz), 3.42–3.48 (m, 2H), 3.14–3.21(m, 2H), 2.82–2.92 (m, 2H), 2.17–2.25 (m, 2H), 1.67–1.82 (m, 5H),1.34–1.42 (m, 1H). IR (KBr, cm⁻¹) 3416, 3058, 2944, 2638, 2538, 1612,1568, 1499, 1474, 1397, 1304, 1255, 1176, 1086, 1017, 841, 807, 776. MS(ES⁺) m/e 526. Anal. Calcd for C₃₀H₃₁N₅O₂S 2HCl C, 60.20; H, 5.57; N,11.70. Found C, 60.08; H, 5.63; N, 11.49. Mp(° C.)=Decomposes at 120.

Example 240 Preparation of1-(3-{4-[5-(4-Phenoxyphenylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 4-phenoxybenzene thiol (0.166 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.161 g (40%) of1-(3-{4-[5-(4-phenoxyphenylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹H NMR (DMSO-d6) δ 7.82 (d, 2H, J=9 Hz), 7.45 (d, 2H, J=9 Hz), 7.34–7.39(m, 2H), 7.09–7.16 (m, 3H), 6.93–7.00 (m, 4H), 4.48 (s, 2H), 4.15 (t,2H, J=6 Hz), 3.41–3.48 (m, 2H), 3.13–3.20 (m, 2H), 2.82–2.91 (m, 2H),2.15–2.22 (m, 2H), 1.65–1.83 (m, 5H), 1.33–1.41 (m, 1H). IR (KBr, cm⁻¹)2936, 2863, 2620, 2499, 2418, 1612, 1582, 1498, 1422, 1232, 1171, 1090,1038, 1005, 961, 833, 758, 693, 503. MS (ES⁺) m/e 502. Anal. Calcd forC₂₉H₃₁N₃O₃S HCl C, 64.73; H, 5.99; N, 7.81. Found C, 64.49; H, 6.01; N,7.75. Mp(° C.)=169.

Example 2411-(3-{4-[5-(2-Phenoxyphenylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 2-phenoxybenzene thiol (0.166 g,0.82 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.166 g (41%) of1-(3-{4[5-(4-phenoxyphenylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹H NMR (DMSO-d6)

7.79 (d, 2H, J=9 Hz), 7.61 (dd, 1H, J=8 Hz), 7.25–7.31 (m, 3H),7.15–7.19 (m, 1H), 7.03–7.12 (m, 3H), 6.90 (dd, 1H, J=2, 8 Hz), 6.84 (d,2H, J=7 Hz), 4.54 (s, 2H), 4.14 (t, 2H, J=6 Hz), 3.42–3.48 (m, 2H),3.14–3.19 (m, 2H), 2.82–2.91 (m, 2H), 2.14–2.21 (m, 2H), 1.66–1.82 (m,5H), 1.43–1.42 (m, 1H). IR (KBr, cm⁻¹) 2949, 2618, 2488, 1612, 1570,1499, 1470, 1298, 1253, 1230, 1175, 1069, 941, 834, 755. MS (ES⁺) m/e502. Anal. Calcd for C₂₉H₃₁N₃O₃S HCl C, 64.73; H, 5.99; N, 7.81. FoundC, 64.44; H, 5.94; N, 7.68. Mp(° C.)=132.

Example 2421-(3-{4-[5-(Benzofuran-2-ylmethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 202b from{5-[4-(3-piperidin-2-yl-propoxy)phenyl][1,3,4]oxadiazol-2-yl}methanol(0.216 g, 0.7 mmol), 2-chloromethlybenzofuran (0.113 g, 0.7 mmol) andsodium hydride (0.027 g, 0.7 mmol). Purification by radialchromatography (eluted with 5% NH₃ in MeOH:CH₂Cl₂) afforded 0.129 g ofthe title compound as an oil that slowly crystallizes out. This materialwas combined with 0.021 g from a previous run, then converted to the HClsalt as described in Example 5 using the acetyl chloride/EtOH method togenerate HCl in situ afforded 0.091 g of1-(3-{4-[5-(benzofuran-2-ylmethoxymethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine.

¹H NMR (DMSO-d6)

7.88 (d, 2H), 7.81 (d, 1H), 7.73 (d, 1H), 7.20–7.33 (m, 2H), 7.11 (d,2H), 6.95 (s, 1H), 4.86 (s, 2H), 4.79 (s, 2H), 4.15 (t, 2H), 3.43–3.50(m, 2H), 3.15–3.23 (m, 2H), 2.83–2.94 (m, 2H), 2.15–2.23 (m, 2H),1.65–1.85 (m, 5H), 1.33–1.45 (m, 1H). MS (ES⁺) m/e 448. Mp(° C.)=138.

Example 2431-(3-{4-[5-(Biphenyl-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from biphenyl-2-thiol (0.152 g, 0.82mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.250 g, 0.74 mmol) and sodium hydride (0.033 g, 0.82 mmol) to afford0.213 g (55%) of1-(3-{4-[5-(biphenyl-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹H NMR (DMSO-d6) δ 7.78 (d, 2H, J=9 Hz), 7.66 (d, 1H, J=8 Hz), 7.29–7.40(m, 5H, 7.20–7.25 (m, 3H), 7.11 (d, 2H, J=9 Hz), 4.39 (s, 2H), 4.15 (t,2H, J=6 Hz), 3.40–3.48 (m, 2H), 3.12–3.21 (m, 2H), 2.81–2.91 (m, 2H),2.12–2.23 (m, 2H), 1.65–1.83 (m, 5H), 1.32–1.41 (m, 1H). IR (KBr, cm⁻¹)3435, 3058, 2947, 2632, 2496, 1614, 1586, 1497, 1466, 1428, 1309, 1249,1176, 1084, 1052, 839, 746, 700. MS (ES⁺) m/e 486. Analytical HPLC:100%. Mp(° C.)=165.

Example 2443-{5-[4-(3-Piperidine-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-indole

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 220 from 3-mercaptoindole (0.252 g, 1.69mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.515 g, 1.53 mmol) and sodium hydride (0.067 g, 1.69 mmol) to afford0.2963 g (43%) of3-{5-[4-(3-piperidine-1-yl-propoxy)phenyl]-[1,3,4]oxadiazol-2-ylmethylsulfanyl}-1H-indole.

¹H NMR (DMSO-d6)

7.767 (d, 2H, J=Hz), 7.38–7.47 (m, 3H), 7.04–7.11 (m, 3H), 6.93–6.97 (m,1H), 4.12 (s, 2H), 4.07 (t, 2H, J=6 Hz), 2.28–2.39 (m, 6H), 1.83–1.90(m, 21), 1.43–1.52 (m, 4H), 1.32–1.40 (m, 2H). IR (KBr, cm⁻¹) 3221,3097, 2933, 2850, 2765, 1609, 1567, 1500, 1463, 1423, 1302, 1256, 1173,1127, 1017, 839, 738. MS (ES⁺) m/e 449, MS (ES⁻) m/e 447. Mp(° C.)=155.

Example 2451-(3-{4-[5-(Benzofuran-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidine

A suspension of 2-[1,2,3]thiazol-4-yl-phenol (0.0.082 g, 0.46 mmol),1-{3-[4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)phenoxy]propyl}piperidine(0.154 g, 0.46 mmol) and potassium carbonate (0.076 g, 0.55 mmol) wasrefluxed for 48 hours then concentrated to an oil. The oil was treatedwith H₂O then extracted twice with EtOAc. The combined organic phaseswere washed with brine, dried over Na₂SO₄, filtered, concentrated to anoil. Purification by radial chromatography on silica gel (eluted with 5%2M NH₃ in MeOH:CH₂Cl₂) followed by conversion to the HCl salt asdescribed in Example 5 using the acetyl chloride/EtOH method to generateHCl in situ afforded 0.074 g (33%) of1-(3-{4-[5-(benzofuran-2-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenoxy}propyl)piperidineas the hydrochloride salt.

¹HNMR (DMSO-d6)

7.71 (d, 2H, J=9 Hz), 7.58 (d, 1H, J=7 Hz), 7.51 (d, 1H, J=7 Hz),7.31–7.35 (m, 2H), 7.14 (s, 1H), 7.05 (d, 2H, J=9 Hz), 4.56 (s, 2H),4.13 (t, 2H, J=6 Hz), 3.39–3.48 (m, 2H), 3.12–3.20 (m, 2H), 2.80–2.92(m, 2H), 2.13–2.22 (m, 2H), 1.65–1.83 (m, 5H), 1.33–1.40 (m, 1H). IR(KBr, cm⁻¹) 2943, 2619, 2503, 1615, 1499, 1446, 1252, 1178, 1055, 944,840, 750, 415. MS (ES⁺) m/e 450.

Example 246 Preparation of(3-{4-[4-benzyl-5-(2-phenoxyethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-dimethyl-amine,oxalic acid salt

a) 4-Hydroxy-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

A solution of (2-phenoxy-ethylsulfanyl)-acetic acid (0.848 g, 4.0 mM)and (2-ethoxy-1-ethoxycarbonyl-1,2-dihdroquinoline, ethyl1,2-dihydro-2-ethoxy-1-quinolinecarboxylate), (EEDQ), (0.989 g, 4.0 mM)in 20 mL acetonitrile and 5 mL THF were stirred together at roomtemperature for 1 hr. 4-Hydroxy-benzoic acid hydrazide (0.608 g, 4.0 mM)was added and the mixture was sonicated for 2 hrs and stirred at roomtemperature for 16 hrs. The mixture was concentrated to low volume andextracted with ethyl acetate. The organic extract was washed with 1NHCl, H₂O, NaHCO₃, brine, dried over magnesium sulfate, filtered, andconcentrated to dryness to give 1.28 g (92%) of 4-hydroxy-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide.

¹H NMR (DMSO-d6) δ 10.2 (s, 1H), 10.1 (s, 1H), 10.0 (s, 1H), 7.7 (d, 2H,J=9 Hz), 7.3 (m, 2H), 6.9 (m, 3H), 6.8 (d, 2H, J=9 Hz), 4.2 (t, 2H, J=6Hz), 3.3 (m, 2H), 3.0 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 3305, 3201, 3003,2918, 2867, 1696, 1623, 1609, 1584, 1517, 1287, 1242, 1229. MS (ESI) m/e347, 345. Anal. Calcd for C₁₇H₁₈N₂O₄S: C, 58.95; H, 5.24; N, 8.09. FoundC, 58.37; H, 5.51; N, 7.19.

b) 4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol

A solution of 4-hydroxy-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (4.87 g, 14.1 mM),triphenyl phosphine (7.38 g, 28.1 mM), and triethylamine (5.14 g, 50.7mM) were stirred together in acetonitrile (15 mL). Carbon tetrachloride(9.17 g, 57.9 mM) was added and the mixture was stirred at roomtemperature for 3 hrs. The material was concentrated to low volume anddiluted with hexane (100 mL), ethyl acetate (6 mL), and ethanol (25 mL).The mixture was sonnicated for 5 minutes and a precipitate formed. Thesolid was collected and dried in vaccuo (30° C.). The solid was slurriedwith 1N HCl, collected and dried to give 3.149 g (68%) of the titlecompound.

¹H NMR (DMSO-d6) δ 7.8 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 6.9 (m,5H), 4.2 (m, 4H), 3.0 (t, 2H, J=6 Hz). IR (KBr, cm⁻¹) 3410, 1762, 1611,1601, 1498, 1242, 1226, 1174, 752. MS (ESI) m/e 329, 327. Anal. Calcdfor C₁₇H₁₆N₂O₃S: C, 62.18; H, 4.91; N, 8.53. Found C, 61.99; H, 5.00; N,7.92. M.P.=172–175° C.

c)4-[4-Benzyl-5-(2-phenoxy-ethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenol

A heterogeneous mixture of4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.657g, 2.0 m) in neat benzylamine (2.0 mL, 18.0 mM) was stirred at 120° C.for 18 h and at 150° C. for 6 h. The reaction mixture was allowed tocool to room temperature, diluted with ethyl acetate, and the organiclayer washed with 1N HCl, water and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford 0.903 gof a yellow gum. Purification by column chromatography on silica gel(isocratic elution with ethyl acetate) afforded 0.383 g (46%) of4-[4-Benzyl-5-(2-phenoxy-ethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenolas a white foam (MP 64–66° C., MW 417.53).

¹H NMR (DMSO-d₆) δ 9.87 (s, 1H), 7.32 (d, 2H, J=8 Hz), 7.27 (m, 5H),6.92 (d, 2H, J=8 Hz), 6.88 (m, 3H), 6.78 (d, 2H, J=9 Hz), 5.34 (s, 2H),4.07 (t, 2H, J=7 Hz), 3.92 (s, 2H), and 2.91 (t, 2H, J=7 Hz). IR (KBr,cm⁻¹) 3050–2470, 1612, 1496, 1453, 1282, 1241, 1172, 840, 754, and 692.MS (ESI) m/e 418, 416. Anal. Calcd for C₂₄H₂₃N₃O₂S: C, 69.04; H, 5.55;N, 10.06; S, 7.68. Found C, 68.39; H, 5.45; N, 9.77; S, 7.52.

d)(3-{4-[4-benzyl-5-(2-phenoxyethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-dimethyl-amine,oxalic acid salt

A heterogeneous mixture of4-[4-Benzyl-5-(2-phenoxy-ethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenol(0.152 g, 0.36 mM), 3-chloro-N,N-dimethylpropylamine hydrochloride(0.063 g, 0.396 mM), and cesium carbonate (0.142 g, 0.432 mM) in 3 mLDMF was stirred at 90–100° C. for 7 h. Triton B (40 weight % in CH₃OH,0.082 mL, 0.18 mM, 0.5 eq) was then added, and the reaction mixtureheated at 90° C. for an additional 1.5 h. The reaction mixture wasallowed to cool to room temperature and diluted with ethyl acetate/H₂O.The solvent layers were separated, the aqueous layer back extracted withethyl acetate, the combined organic extracts washed with water,saturated NaHCO₃ solution, 1N NaOH, and brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to afford 0.136 g ofa yellow gum. Purification by column chromatography on silica gel(isocratic elution with ethyl acetate followed by 9:1 CHCl₃/2.0 Mammonia in methanol) afforded 0.101 g (55%) of(3-{4-[4-benzyl-5-(2-phenoxyethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-dimethyl-amineas an oily gum. The gum (0.099 g, 0.196 mM) was dissolved in 2 mLacetone, and oxalic acid (0.019 g, 0.216 mM), dissolved in 1 mL acetone,was added with rapid stirring at room temperature followed by theaddition of diethyl ether/hexane (1:1, 2 mL). Filtered the resultantthick precipitate, washed the collected solid with acetone and diethylether, and dried in vacuo at 40° C. to afford 0.104 g (89%) of(3-{4-[4-benzyl-5-(2-phenoxyethylsulfanylmethyl)-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-dimethyl-amine,oxalic acid salt as an off-white solid (MP 88–92° C., MW oxalate salt592.72, MW free amine 502.68).

¹H NMR (DMSO-d₆) δ 7.46 (d, 2H, J=9 Hz), 7.26 (m, 5H), 6.98 (d, 2H, J=9Hz), 6.92 (m, 3H), 6.88 (d, 2H, J=9 Hz), 5.37 (s, 2H), 4.06 (m, 4H),3.95 (s, 2H), 3.13 (m, 2H), 2.91 (t, 2H, J=6 Hz), 2.74 (s, 6H), and 2.06(m, 2H). IR (KBr, cm⁻¹) 3037–2870, 2700–2500, 1721, 1611, 1478, 1248,1176, 1036, 704, and 475. MS (ESI) m/e 503. Anal. Calcd forC₂₉H₃₄N₄O₂S.C₂H₂O₄: C, 62.82; H, 6.12; N, 9.45; S, 5.41. Found C, 56.37;H, 5.27; N, 8.26; S, 5.37. Analytical HPLC: 88% purity.

Example 247 Preparation ofDimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-amine,oxalic acid salt

a) 4-Hydroxy-benzoic acidM-[2-(2-phenoxyethylsulfanyl)-acetyl]-hydrazide

The above compound was prepared in an identical manner as exemplified inExample 246a.

b) 4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in an identical manner as exemplified inExample 246b.

c)4-[5-(2-Phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenol

A heterogeneous mixture of4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.985g, 3.0 mM) in neat aniline (2.0 mL, 22.0 mM) was stirred at 150° C. for12 h. The reaction mixture was allowed to cool to room temperature,diluted with ethyl acetate, and the organic layer washed with 1N HCl,water and brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford a light tan solid. Added ethyl acetateand diethyl ether to the solid, sonicated, filtered, washed thecollected solid with ethyl acetate and diethyl ether, and dried in vacuoat 40° C. to afford 0.99 g (82%) of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenolas a light lavender solid (MP 214–216° C., MW 403.51.

¹H NMR (DMSO-d₆) δ 9.83 (s, 1H), 7.51 (m, 3H), 7.38 (m, 2H), 7.26 (t,2H, J=7 Hz), 7.12 (d, 2H, J=9 Hz), 6.91 (t, 1H, J=7 Hz), 6.87 (d, 2H,J=10 Hz), 6.66 (d, 2H, J=9 Hz), 4.02 (t, 2H, J=6 Hz), 3.80 (s, 2H), and2.85 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3050–2487, 1607, 1585, 1499, 1469,1285, 1244, 1176, 1037, and 691. MS (ESI) m/e 404, 402. Anal. Calcd forC₂₃H₂₁N₃O₂S: C, 68.46; H, 5.25; N, 10.41; S, 7.95. Found C, 68.58; H,5.26; N, 10.40; S, 7.94.

d)Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-amine,oxalic acid salt

A heterogeneous mixture of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenol(0.161 g, 0.4 mM), 3-chloro-N,N-dimethylpropylamine hydrochloride (0.07g, 0.44 mM), and Triton B (40 weight % in CH₃OH, 0.418 mL, 0.92 mM) in 3mL DMF was stirred at 90° C. for 4.5 h. Cesium carbonate (0.099 g, 0.3mM, 0.75 eq) was then added, and the reaction mixture heated at 90° C.for an additional 2.5 h. The reaction mixture was allowed to cool toroom temperature and diluted with ethyl acetate/H₂O. The solvent layerswere separated, the aqueous layer back extracted with ethyl acetate, thecombined organic extracts washed with water, saturated NaHCO₃ solution,1N NaOH, and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford 0.155 g of a lavender gum. Purificationby column chromatography on silica gel (isocratic elution with ethylacetate followed by 95:5 CHCl₃/2.0 M ammonia in methanol) afforded 0.137g (70%) ofDimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-amineas an off-white. The gum (0.135 g, 0.276 mM) was dissolved in 2 mLacetone, and oxalic acid (0.028 g, 0.304 mM), dissolved in 1 mL acetone,was added with rapid stirring at room temperature followed by theaddition of diethyl ether/hexane (1:2, 3 mL). Filtered the resultantthick precipitate, washed the collected solid with diethyl ether andhexane, and dried in vacuo at 40° C. to afford 0.153 g (96%) ofDimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-4-phenyl-4H-[1,2,4]triazol-3-yl]-phenoxy}-propyl)-amine,oxalic acid salt as a white solid (MP 120–123° C., MW oxalate salt578.70, MW free amine 488.66).

¹H NMR (DMSO-d6) δ 7.51 (m, 3H), 7.41 (m, 2H), 7.34 (m, 2H), 7.25 (d,2H, J=9 Hz), 6.91 (t, 1H, J=7 Hz), 6.88 (d, 2H, J=9 Hz), 6.87 (d, 2H,J=7 Hz), 4.01 (m, 4H), 3.81 (s, 2H), 3.10 (m, 2H), 2.86 (t, 2H, J=6 Hz),2.72 (s, 6H), and 2.03 (m, 2H). IR (KBr, cm⁻¹) 2950–2870, 2700–2500,1612, 1600, 1586, 1497, 1477, 1403, 1258, 1246, 1181, 704, and 694. MS(ESI) m/e 489. Anal. Calcd for C₂₈H₃₂N₄O₂S.C₂H₂O₄: C, 62.27; H, 5.92; N,9.68; S, 5.54. Found C, 60.86; H, 5.40; N, 9.40; S, 5.61. AnalyticalHPLC: 94% purity.

Example 248 Preparation ofDimethyl-(3-{4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

a) 4-Hydroxy-benzoic acid N′-(4-phenoxy-benzoyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 4-phenoxybenzoic acid (1.09 g,5.0 mM) to afford 1.01 g (58%) of 4-Hydroxy-benzoic acidN′-(4-phenoxy-benzoyl)-hydrazide as a white solid (MP 203–205° C., MW348.36).

¹HNMR (DMSO-d₆) δ 10.32 (s, 1H), 10.19 (s, 1H), 10.08 (s, 1H), 7.93 (d,2H, J=9 Hz), 7.78 (d, 2H, J=Hz), 7.44 (t, 2H, J=8 Hz), 7.22 (t, 1H, J=8Hz), 7.10 (d, 2H, J=8 Hz), 7.06 (d, 2H, J=9 Hz), and 6.83 (d, 2H, J=9Hz). IR (KBr, cm⁻¹) 3216, 1656, 1614, 1586, 1573, 1515, 1488, 1284,1247, 1169, 844, 753, and 693. MS (ESI) m/e 349, 347. Anal. Calcd forC₂₀H₁₆N₂O₄: C, 68.96; H, 4.63; N, 8.04. Found C, 68.65; H, 4.68; N,8.00.

b) 4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-hydroxy-benzoic acidN′-(4-phenoxy-benzoyl)-hydrazide (1.01 g, 2.9 mM), triphenylphosphine(1.54 g, 5.8 mM), and triethylamine (1.46 mL, 10.44 mM) to afford 0.65 g(68%) of 4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenol as awhite solid (MP 204–206° C., MW 330.35).

¹H NMR (DMSO-d6) δ 10.31 (s, 1H), 8.07 (d, 2H, J=9 Hz), 7.92 (d, 2H, J=9Hz), 7.45 (t, 2H, J=8 Hz), 7.23 (t, 1H, J=7 Hz), 7.15 (d, 2H, J=9 Hz),7.13 (d, 2H, J=9 Hz), and 6.95 (d, 2H, J=9 Hz). IR (KBr, cm⁻¹) 3125,1740, 1612, 1588, 1492, 1379, 1287, 1240, 1167, 1099, 1068, 868, 847,746, 695, and 510. MS (ESI) m/e 331, 329. Anal. Calcd for C₂₀H₁₄N₂O₃: C,72.72; H, 4.27; N, 8.48. Found C, 70.35; H, 4.66; N, 7.27.

c)Dimethyl-(3-{4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, from4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenol (0.298 g, 0.9 mM)and purified by Chromatotron radial chromatography on silica gel(isocratic elution with 95:5 CH₂Cl₂/2.0 M ammonia in methanol) to afford0.295 g (780%) ofDimethyl-(3-{4-[5-(4-phenoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas a white solid (MP 95° C., MW 415.50).

¹H NMR (CDCl₃) δ 8.07 (d, 2H, J=9 Hz), 8.04 (d, 2H, J=9 Hz), 7.40 (t,2H, J=8 Hz), 7.20 (t, 1H, J=8 Hz), 7.10 (d, 2H, J=9 Hz), 7.09 (d, 2H,J=9 Hz), 7.02 (d, 2H, J=9 Hz), 4.12 (t, 2H, J=6 Hz), 2.61 (t, 2H, J=7Hz), 2.38 (s, 6H), and 2.08 (m, 2H). IR (KBr, cm⁻¹) 2954, 2821, 2764,1610, 1488, 1417, 1298, 1246, 1171, 1068, 996, 871, 835, 742, 689, 670,and 510. MS (ESI) m/e 416. Anal. Calcd for C₂₅H₂₅N₃O₃: C, 72.27; H,6.06; N, 10.11. Found C, 71.99; H, 6.29; N, 9.94. Analytical HPLC: 100%purity.

Example 249 Preparation of{3-[4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethyl-amine

a) 4-Hydroxy-benzoic acid N-(2-biphenyl-4-yl-acetyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 4-biphenylacetic acid (1.08 g,5.0 m) to afford 1.58 g (91%) of 4-Hydroxy-benzoic acidN′-(2-biphenyl-4-yl-acetyl)-hydrazide as a white solid (MP 234–239° C.dec, MW 346.13).

¹H NMR (DMSO-d₆) δ 10.10 (s, 1H), 10.09 (s, 1H), 10.05 (s, 1H), 7.73 (d,2H, J=9 Hz), 7.64 (d, 2H, J=7 Hz), 7.60 (d, 2H, J=8 Hz), 7.44 (t, 2H,J=8 Hz), 7.43 (d, 2H, J=8 Hz), 7.34 (t, 1H, J=7 Hz), 6.80 (d, 2H, J=9Hz), and 3.56 (s, 2H). IR (KBr, cm⁻¹) 3265, 1663, 1605, 1572, 1485,1281, 1230, 847, 740, and 497. MS (ESI) m/e 347, 345. Anal. Calcd forC₂₁H₁₈N₂O₃: C, 72.82; H, 5.24; N, 8.09. Found C, 71.83; H, 5.35; N,8.31.

b) 4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-Hydroxy-benzoic acidN′-(2-biphenyl-4-yl-acetyl)-hydrazide (1.56 g, 4.5 mM),triphenylphosphine (2.38 g, 9.0 mM), and triethylamine (2.26 mL, 16.2mM) to afford 0.798 g (54%) of4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenol as a lightyellow solid (MP 252–255° C., MW 328.37).

¹H NMR (DMSO-d₆) δ 10.24 (s, 1H), 7.76 (d, 2H, J=9 Hz), 7.63 (m, 4H),7.43 (m, 4H), 7.33 (t, 1H, J=7 Hz), 6.90 (d, 2H, J=9 Hz), and 4.34 (s,2H). IR (KBr, cm⁻¹) 3055, 1612, 1569, 1497, 1431, 1370, 1285, 1238,1173, 1087, 1030, 862, 819, 757, 692, and 522. MS (ESI) m/e 329, 327.Anal. Calcd for C₂₁H₁₆N₂O₂: C, 76.81; H, 4.91; N, 8.53. Found C, 76.41;H, 5.03; N, 8.19.

c){3-[4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethyl-amine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 50f, from4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.328 g, 1.0mM), 3-chloro-N,N-dimethylpropylamine hydrochloride (0.174 g, 1.1 mM),and sodium hydride (0.092 g, 2.3 mM) in 7 mL DMF to afford 0.461 g of abrown gum. A second lot of the above compound was prepared in a mannersimilar to that exemplified for the preparation of Example 50f, from4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.164 g, 0.5mM), 3-chloro-N,N-dimethylpropylamine hydrochloride (0.087 g, 0.55 mM),and cesium carbonate (0.197 g, 0.6 mM) in 3 mL DMF to afford 0.173 g ofa yellow-orange solid. The combined lots were purified by Chromatotronradial chromatography on silica gel (isocratic elution with 97:3Et₂O/2.0 M ammonia in methanol) to afford 0.113 g (18%) of{3-[4-(5-Biphenyl-4-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-dimethyl-amineas a white solid (95–97° C., MW 413.52).

¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=9 Hz), 7.58 (d, 2H, J=8 Hz), 7.57 (d,2H, J=7 Hz), 7.44 (t, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 7.34 (t, 1H,J=7 Hz), 6.96 (d, 2H, J=9 Hz), 4.31 (s, 2H), 4.12 (t, 2H, J=6 Hz), 2.81(m, 2H), 2.53 (bs, 6H), and 2.20 (m, 2H). IR (KBr, cm⁻¹) 2943, 2857,2813, 2762, 1613, 1568, 1501, 1473, 1249, 1174, 1035, 832, 757, 739, and699. MS (ESI) m/e 414, 412. Anal. Calcd for C₂₆H₂₇N₃O₂: C, 75.52; H,6.58; N, 10.16. Found C, 75.12; H, 6.54; N, 10.01. Analytical HPLC: 100%purity.

Example 250 Preparation of1-(2-Dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-ureamaleate

a)Benzhydrylidene-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-amine

Combined 5-(4-bromo-phenyl)-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole(0.5 g, 1.28 mmol, 1 eq., Example 268f), benzophenone imine (0.30 g,1.54 mmol, 1.2 eq.), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 3.2pmol, 0.25%), (±)-BINAP (6 mg, 9.60 □mol, 0.75%), and sodiumtert-butoxide (0.17 g, 1.79 mmol, 1.4 eq.) in toluene (10 mL) and heatedto 105° C. overnight. Diluted the cooled reaction with EtOAc and washedwith water. The organic layer was collected, dried over MgSO₄, filtered,and the solvent removed leaving an orange oil which was purified vianormal phase chromatography using 25% EtOAc in hexanes as the mobilephase leavingbenzhydrylidene-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-amine(0.63 g, 100% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.67 (m, 2H), 7.48 (m, 7H), 7.25 (m, 6H), 6.93 (m,3H), 6.77 (m, 2H), 4.16 (t, 2H, J=7 Hz), 4.01 (s, 2H), 2.98 (t, 2H, J=7Hz). IR (CHCl₃, cm⁻¹) 3003.6, 1600.7, 1570.8, 1494.6, 1293.1, 1241.MS(ES⁺) m/e 491 [M+H]⁺. Anal. Calcd. for C₃₁H₂₆N₂O₂S C, 75.89; H, 5.34;N, 5.71. Found C, 75.50; H, 5.42; N, 5.63. M.P.=86–90° C.

b) 4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenylamine

A THF solution (15 mL) ofbenzhydrylidene-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-amine(2.0 g, 4.08 mmol, 1 eq.) was treated with 0.75 mL of 2 M aqueous HCland the solution allowed to stir at room temperature for 1 hour. Dilutedwith 0.5 M aqueous HCl and extracted with EtOAc. Collected the organiclayer, dried over MgSO₄, filtered, and removed the solvent in vacuoleaving an orange oil which was purified via normal phase chromatographyusing a step gradient of EtOAc in hexanes as the mobile phase resultingin 4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenylamine (1.2 g,90% yield) as yellow solid after removal of the solvent.

¹H NMR (DMSO-d6) δ 7.27 (m, 4H), 6.93 (m, 3H), 6.60 (m, 21), 4.16 (t,2H, J=7 Hz), 4.0 (s, 2H), 2.98 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3461.7,3339, 1627.5, 1613.9, 1601, 1505.7, 1488.7, 1299, 1242, 1231.3, 1175,1099.3, 828.1, 757.8, 749.9. MS(ES⁺) m/e 327 [M+H]⁺. Anal. Calcd. forC₁₈H₁₈N₂O₂S C, 66.23; H, 5.56; N, 8.58. Found C, 65.98; H, 5.56; N,8.45. M.P.=110–111° C.

c) {-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamicacid ethyl ester

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101a from4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenylamine (1.63 g,4.99 mmol, 1 eq.) and ethyl chloroformate (0.81 g, 7.49 mmol, 1.5 eq.)to produce{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.99 g, 100% yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 9.81 (s, 1H), 7.57 (m, 4H), 7.47 (s, 1H), 7.27 (m,2H), 6.93 (m, 3H), 4.15 (m, 4H), 4.04 (s, 2H), 3.0 (t, 2H, J=7 Hz), 1.25(t, 3H, J=7 Hz). MS(ES⁺) m/e 399 [M+H]⁺. MS(ES⁻) m/e 397 [M−H]⁻.

d) Preparation of1-(2-dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-ureamaleate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.0 g, 2.5 mmol, 1 eq.) and N,N-dimethylethylenediamine(0.26 g, 3.0 mmol, 1.2 eq.) to produce1-(2-dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl)-phenyl}-urea(1.05 g, 95% yield) as a yellow oil.

An EtOAc solution of1-(2-dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-urea(0.51 g, 1.16 mmol, 1 eq.) was treated dropwise with an EtOAc solutionof maleic acid (0.15 g, 1.28 mmol, 1.1 eq.). Removed the EtOAc in vacuoand added Et₂O and boiled the resulting gum until1-(2-dimethylamino-ethyl)-3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-ureamaleate (0.43 g, 68% yield) was obtained as a yellow solid.

¹H NMR (DMSO-d6) δ 8.98 (s, 1H), 7.54 (m, 4H), 7.44 (s, 1H), 7.27 (m,2H), 6.93 (m, 3H), 6.41 (t, 1H, J=6 Hz), 6.03 (s, 2H), 4.17 (t, 2H, J=7Hz), 4.04 (s, 2), 3.44 (m, 2H), 3.15 (m, 2H), 2.99 (t, 2H, J=7 Hz), 2.82(s, 6H). IR (KBr, cm⁻¹) 3402.4, 1695.6, 1607.6, 1547.2, 1498.6, 1465,1359.6, 1322.2, 1227.1, 867.3, 754.4. MS(ES⁺) m/e 441 [M+H]⁺. MS(ES⁻)m/e 439 [M−H]⁻. Anal. Calcd. for C₂₇H₃₂N₄O₇S C, 58.26; H, 5.79; N,10.07. Found C, 57.68; H, 5.58; N, 9.88. Analytical LC/MS 100% (diodearray detector). M.P.=105–107° C.

Example 251 Preparation of1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-pyrrolidin-1-ylmethyl-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.0 g, 2.5 mmol, 1 eq.) and 1-(2-aminoethyl)pyrrolidine(0.34 g, 3.0 mmol, 1.2 eq.) to produce1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-pyrrolidin-1-ylmethyl-urea(1.14 g, 97% yield) as a yellow oil.

An EtOAc solution of the urea was treated with an EtOAc solution ofoxalic acid (0.20 g, 1.1 eq.) producing1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-pyrrolidin-1-ylmethyl-ureaoxalate (0.57 g) as an off-white solid that was collected by filtration.

¹H NMR (DMSO-d6) δ 9.37 (s, 1H), 7.53 (bs, 4H), 7.43 (s, 1H), 7.27 (m,2H), 7.09 (bs, 1H), 6.93 (m, 3H), 4.17 (t, 2H, J=7 Hz), 4.04 (s, 2H),3.41 (bs, 2H), 3.22 (m, 6H), 2.99 (t, 2H, J=7 Hz), 1.92 (bs, 4H). IR(KBr, cm1) 3367.2, 3283.3, 1733.7, 1688.4, 1587.2, 1536, 1504.2, 1317.2,1233.3, 711.6. MS(ES⁺) m/e 467 [M+H]⁺. MS(ES⁻) m/e 465 [M−H]⁻. Anal.Calcd. for C₂₇H₃₂N₄O₇S C, 58.26; H, 5.79; N, 10.07. Found C, 57.82; H,5.76; N, 9.86. Analytical LC/MS 95% purity (diode array detector).M.P.=124–126° C.

Example 252 Preparation of1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-piperidin-1-ylmethyl-urea

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.75 g, 4.39 mmol, 1 eq.) and 1-(2-aminoethyl)piperidine(0.68 g, 5.27 mmol, 1.2 eq.) to obtain1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-piperidin-1-ylmethyl-urea(0.88 g, 42% yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 8.85 (s, 1H), 7.50 (m, 5H), 7.27 (m, 2H), 6.92 (m,3H), 6.10 (t, 1H, J=6 Hz), 4.17 (t, 2H, J=7 Hz), 4.03 (s, 2H), 3.19 (m,2H), 2.99 (t, 2H, J=7 Hz), 2.34 (m, 6H), 1.51 (m, 4H), 1.38 (m, 2H). IR(CHCl₃, cm⁻¹) 2941.6, 1684.5, 1601, 1587.4, 1520.3, 1504.9, 1498.4,1243.7. MS(ES⁺) m/e 481 [M+H]⁺. MS(ES⁻) m/e 479 [M−H]⁻. Analytical LC/MS100% purity (diode array detector). M.P.=84–87° C.

Example 253 Preparation of1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-ureaoxalate

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101e from{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (0.55 g, 1.38 mmol, 1 eq.) and 1-(3-aminopropyl)pyrrolidine(0.21 g, 1.66 mmol, 1.2 eq.) to produce1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-urea(0.42 g, 64% yield) as a yellow oil.

An EtOAc solution of the free base was treated with an EtOAc solution ofoxalic acid (0.09 g, 1.1 eq.) producing1-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-ureaoxalate (0.46 g) as a light yellow solid.

¹H NMR (DMSO-d6) δ 9.25 (s, 1H), 7.53 (bs, 4H), 7.42 (s, 1H), 7.27 (m,2), 6.93 (m, 4H), 4.17 (t, 2H, J=7 Hz), 4.04 (s, 2H), 3.24 (b, 4H), 3.16(m, 4H), 2.99 (t, 2H, J=7 Hz), 1.92 (bs, 4H), 1.81 (m, 2H). IR (KBr,cm⁻¹) 3383, 3039.7, 1688.7, 1586.4, 1535.5, 1504.4, 1413.8, 1317.3,1236.1, 840, 756.6, 694.7. MS(ES⁺) m/e 481 [M+H]⁺. MS(ES⁻) m/e 479[M−H]⁻. Analytical LC/MS 85% purity (diode array detector).

Example 254 Preparation of1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-dimethylamino-ethyl)-urea

a) 2-(Benzofuran-2-ylmethoxymethyl)-5-(4-bromo-phenyl)-oxazole

A THF solution of 1-benzofuran-2-ylmethanol (2.2 g, 14.85 mmol, 1 eq.)was treated with NaH (0.65 g, 60% in oil, 16.34 mmol, 1.1 eq.) andstirred at room temperature for 5 minutes before5-(4-bromo-phenyl)-2-chloromethyl-oxazole (4.05 g, 14.85 mmol, 1 eq.)was added as a solid. The reaction was allowed to stir overnight at roomtemperature. The solvent was removed in vacuo and the oil dissolved inEtOAc and washed with water and brine. The organic layer was collected,dried over MgSO₄, filtered, and the solvent removed leaving a brown oilthat was purified by normal phase chromatography using a step gradientof EtOAc in hexanes as the mobile phase. Removal of the solvent andrecrystallization from Et₂O/hexanes left2-(benzofuran-2-ylmethoxymethyl)-5-(4-bromo-phenyl)-oxazole (3.82 g, 67%yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 7.74 (s, 1H), 7.65 (m, 5H), 7.55 (m, 1H), 7.27 (m,2H), 6.95 (s, 1H), 4.76 (s, 2H), 4.71 (s, 2H). IR (KBr, cm⁻¹) 3096.5,1480.8, 1405, 1067.7, 1009.9, 940.5, 821.4, 759.5, 503.6. MS(FAB⁺) m/e384, 386 [M+H]⁺. Analytical LC/MS 100% purity (diode array detector).M.P.=80–82° C.

b)Benzhydrylidene-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-amine

The above compound was prepared in a manner similar to that exemplifiedin example 250a from2-(benzofuran-2-ylmethoxymethyl)-5-(4-bromo-phenyl)-oxazole (4.0 g,10.41 mmol, 1 eq.), benzophenone imine (2.26 g, 12.49 mmol, 1.2 eq.),and sodium tert-butoxide (1.40 g, 14.57 mmol, 1.4 eq.) to producebenzhydrylidene-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-amine(4.72 g, 94% yield) as a yellow foam.

¹H NMR (DMSO-d6) δ 7.64 (m, 3H), 7.51 (m, 7H), 7.26 (m, 7H), 6.95 (s,1H), 6.77 (m, 2H), 4.73 (s, 2H), 4.66 (s, 2H). MS(ES⁺) m/e 485 [M+H]⁺.

c) 4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenylamine

The above compound was prepared in a manner similar to that exemplifiedin Example 250b frombenzhydrylidene-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-amine(4.6 g, 9.49 mmol, 1 eq.) and 2M aqueous HCl (1.5 mL) to produce4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenylamine (2.78 g,91% yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 7.63 (m, 1H), 7.56 (m, 1H), 7.28 (m, 5H), 6.95 (s,1H), 6.61 (m, 2H), 5.46 (s, 2H), 4.73 (s, 2H), 4.64 (s, 2H). IR (KBr,cm⁻¹) 3322, 3222.3, 2909.7, 1610, 1502.3, 1451.8, 1437.7, 1363.7,1281.9, 1236.9, 1129.5, 1077.6, 943.7, 808.1, 755.2, 687.4, 520.2.MS(ES⁺) m/e 321 [M+H]⁺, 131. Anal. Calcd. for C₁₉H₁₆N₂O₃ C, 71.24; H,5.03; N, 8.74. Found C, 71.07; H, 5.03; N, 8.72. Analytical LC/MS 100%purity (diode array detector). M.P.=96–98° C.

d) {4-[2-Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-carbamicacid ethyl ester

This above compound was prepared in a manner similar to that exemplifiedin Example 101a from4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenylamine (2.54 g,7.93 mmol, 1 eq.) and ethyl chloroformate (1.29 g, 11.9 mmol, 1.5 eq.)to produce{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (3.08 g, 99% yield) as a yellow solid.

¹H NMR (DMSO-d6)

9.82 (s, 1H), 7.58 (m, 7H), 7.27 (m, 2H), 6.96 (s, 1H), 4.75 (s, 2H),4.69 (s, 2H), 4.14 (q, 2H, J=7 Hz), 1.25 (t, 3H, J=7 Hz). IR (CHCl₃,cm⁻¹) 3434, 3010.7, 1733, 1600.3, 1586.6, 1521.5, 1453.9, 1416.2,1316.6, 1255.1, 1224.7, 1205.9, 1135, 1069.2, 943.6, 838.8, 818.4.MS(ES⁺) m/e 393 [M+H]⁺, 131. MS(ES⁻) m/e 391 [M−H]⁻, 131. Anal. Calcd.for C₂₂H₂₀N₂O₅ C, 67.34; H, 5.14; N, 7.14. Found C, 67.65; H, 5.08; N,7.10. Analytical LC/MS 100% purity (diode array detector).

e) Preparation of1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-dimethylamino-ethyl)-urea

The above compound was prepared in a manner similar to that exemplifiedin Example 101e from{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.0 g, 2.55 mmol, 1 eq.) and N,N-dimethylethylenediamine(0.27 g, 3.06 mmol, 1.2 eq.) to produce1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-dimethylamino-ethyl)-urea(0.72 g, 65% yield) as an off-white solid when triturated with hot EtOAcand cooled.

¹H NMR (DMSO-d6) δ 8.83 (s, 1H), 7.63 (m, 1H), 7.5 (m, 6H), 7.27 (2H),6.96 (s, 1H), 6.14 (t, 1H, J=6 Hz), 4.75 (s, 2H), 4.68 (s, 2H), 3.18 (m,2H), 2.32 (t, 2H, J=7 Hz), 2.17 (s, 6H). IR (KBr, cm⁻¹) 3311.1, 2938.4,2902.9, 2860.3, 2819.1, 1631.2, 1585.8, 1504.6, 1455.8, 1417.7, 1310.7,1256.1, 1131.2, 1074, 989.8, 943.2, 839.1, 805.3, 749.9. MS(ES⁺) m/e 435[M+H]⁺. MS(ES⁻) m/e 433 [M−H]⁻. Anal. Calcd. for C₂₄H₂₆N₄O₄ C, 66.34; H,6.03; N, 12.89. Found C, 66.55; H, 5.99; N, 12.68. Analytical LC/MS 100%purity (diode array detector). M.P.=150–154° C.

Example 255 Preparation of1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea

The above compound was prepared in a manner similar to that exemplifiedin Example 101e from{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.0 g, 2.55 mmol, 1 eq.) and N-(2-aminoethyl)pyrrolidine(0.35 g, 3.06 mmol, 1.2 eq.) to produce1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea(0.86 g, 73% yield) as a white solid.

¹H NMR (DMSO-d6)

8.84 (s, 1H), 7.63 (m, 1H), 7.5 (m, 6H), 7.27 (m, 2H), 6.96 (s, 1H),6.17 (t, 1H, J=6 Hz), 4.75 (s, 2H), 4.68 (s, 2H), 3.2 (m, 2H), 2.46 (m,6H), 1.70 (bs, 4H). IR (KBr, cm⁻¹) 3346, 2962.2, 2798.2, 1649.4, 1558.4,1525.5, 1453.9, 1413.1, 1313.4, 1242.1, 1079.8, 754.1. MS(ES⁺) m/e 461[M+H]⁺. MS(ES⁻) m/e 459 [M−H)⁻. Analytical LC/MS 100% purity (diodearray detector). M.P.=124–126° C.

Example 256 Preparation of1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea

The above compound was prepared in a manner similar to that exemplifiedin Example 101 e from{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-carbamic acidethyl ester (1.0 g, 2.55 mmol, 1 eq.) and N-(2-aminoethyl)piperidine(0.39 g, 3.06 mmol, 1.2 eq.) to produce1-{4-[2-(benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea(0.60 g, 50% yield) as a light yellow solid on tituration with Et₂O.

¹H NMR (DMSO-d6) δ 8.86 (s, 1H), 7.63 (m, 1H), 7.5 (m, 6H), 7.27 (m,2H), 6.96 (s, 1H), 6.1 (t, 1H, J=6 Hz), 4.75 (s, 2H), 4.68 (s, 2H), 3.19(m, 2H), 2.34 (m, 6H), 1.51 (m, 4H), 1.39 (m, 2H). IR (KBr, cm⁻¹)3323.1, 2923.8, 2856, 2786.8, 1656.3, 1554.3, 1452.8, 1410.3, 1309.8,1232.5, 1136.1, 1069.6, 941.7, 839.6, 742.2. MS(ES⁺) 475 [M+H]⁺. MS(ES⁻)473 [M−H]⁻. Anal. Calcd. for C₂₇H₃₀N₄O₄ C, 68.34; H, 6.37; N, 11.81.Found C, 68.05; H, 6.12; N, 11.69. Analytical LC/MS 100% purity (diodearray detector). M.P.=102–104° C.

Example 257 Preparation of1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-imidazolidin-2-one

a) 4-[3-(2-Chloro-ethyl)-ureido]-benzoic acid methyl ester

A THF solution of methyl 4-aminobenzoate (14.05 g, 92.91 mmol, 1 eq.)was treated with 2-chloroethyl isocyanate (10 g, 94.77 mmol, 1.02 eq.)and stirred overnight at room temperature. Removed the solvent andrecrystallized the orange solid from EtOAc leaving4-[3-(2-chloro-ethyl)-ureido]-benzoic acid methyl ester (16.41 g, 69%yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 9.08 (s, 1H), 7.84 (d, 2H, J=9 Hz), 7.52 (d, 2H, J=9Hz), 6.55 (t, 1H, J=6 Hz), 3.8 (s, 3H), 3.67 (t, 2H, J=7 Hz), 3.44 (m,2H). IR (KBr, cm⁻¹) 3339.2, 3288.1, 1714.6, 1639.2, 1596, 1565.3, 1438,1282.8, 1243.6, 1170.3, 1108.2. MS(ES⁺) m/e 257, 259 [M+H]⁺. AnalyticalLC/MS 100% purity (light scattering). M.P.=163–165° C.

b) 4-(2-Oxo-imidazolidin-1-yl)-benzoic acid methyl ester

A suspension of NaH (5.24 g, 60% in oil, 130.89 mmol, 2.1 eq.) in THFwas treated dropwise with a THF solution of4-[3-(2-chloro-ethyl)-ureido]-benzoic acid methyl ester (16 g, 62.33mmol, 1 eq.) and stirred for 1 hour at room temperature and then 1 hourat reflux. The solvent was removed in vacuo and the residue dissolved inCH₂Cl₂ and washed with water. The organic layer was collected, driedover MgSO₄, and the solvent removed leaving a tan solid which wasrecrystallized from EtOAc/MeOH to produce4-(2-oxo-imidazolidin-1-yl)-benzoic acid methyl ester (8.22 g, 60%yield) as an off-white solid.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 7.23 (s,1H), 3.9 (m, 2H), 3.81 (s, 3H), 3.43 (t, 2H, J=8 Hz). IR (KBr, cm⁻¹)3241.8, 3100.1, 1721.5, 1680.8, 1431.8, 1284.6, 1264.4, 1182.2, 1109.9,853.4. MS(ES⁺) m/e 221 [M+H]⁺. Anal. Calcd. for C₁₁H₁₂N₂O₃ C, 59.99; H,5.49; N, 12.72. Found C, 60.16; H, 5.38; N, 12.64. Analytical LC/MS 100%purity (diode array and light scattering detection). M.P.>200° C.

c) 4-(2-Oxo-imidazolidin-1-yl)-benzoic acid hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101b from4-(2-oxo-imidazolidin-1-yl)-benzoic acid methyl ester (8.18 g, 37.14mmol, 1 eq.) and hydrazine (11.90 g, 371.4 mmol, 10 eq.) except thatMeOH and THF were used as solvents to produce4-(2-oxo-imidazolidin-1-yl)-benzoic acid hydrazide (3.36 g, 41% yield)as an off-white solid.

¹H NMR (DMSO-d6) δ 9.61 (s, 1H), 7.79 (d, 2H, J=9 Hz), 7.6 (d, 2H, J=9Hz), 7.1 (s, 1H), 4.41 (s, 2H), 3.87 (t, 2H, J=8 Hz), 3.41 (t, 2H, J=8Hz). IR (KBr, cm⁻¹) 3298.7, 3213.8, 3198.1, 1700.3, 1635.3, 1606,1487.2, 1443.8, 1429.2, 1407.1, 1311.1, 1261.5, 940.1, 843.7, 745.4.MS(ES⁺) m/e 221 [M+H]⁺. M.P.>200° C.

d) 4-(2-Oxo-imidazolidin-1-yl)-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 101c from4-(2-oxo-imidazolidin-1-yl)-benzoic acid hydrazide (2.0 g, 9.08 mmol, 1eq.) and (2-phenoxyethylthio)acetic acid (1.93 g, 9.08 mmol, 1 eq.) toproduce 4-(2-oxo-imidazolidin-1-yl)-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (2.79 g, 74% yield) asa tan solid.

¹H NMR (DMSO-d6) δ 10.3 (s, 1H), 10 (s, 1H), 7.86 (d, 2H, J=9 Hz), 7.66(d, 2H, J=9 Hz), 7.29 (m, 2H), 7.16 (s, 1H), 6.95 (m, 3H), 4.2 (t, 2H,J=7 Hz), 3.9 (m, 2H), 3.43 (m, 4H), 3.05 (m, 2H). IR (KBr, cm⁻¹) 3300.6,1696.1, 1656.6, 1611.3, 1484, 1241, 1032.7, 745.4. MS(ES⁺) m/e 415[M+H]⁺. Anal. Calcd. for C₂₀H₂₂N₄O₄S C, 57.96; H, 5.35; N, 13.52. FoundC, 57.57; H, 5.4; N, 13.41.

e)1-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-imidazolidin-2-one

The above compound was prepared in a similar manner to that exemplifiedfor the preparation of Example 101d from4-(2-oxo-imidazolidin-1-yl)-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (2.6 g, 6.27 mmol, 1eq.) to produce1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-imidazolidin-2-one(1.02 g, 41% yield) as a brown solid.

¹H NMR (DMSO-d6) δ 7.89 (d, 2H, J=9 Hz), 7.77 (d, 2H, J=9 Hz), 7.25 (m,3H), 6.93 (m, 3H), 4.2 (m, 4H), 3.92 (m, 2H), 3.44 (m, 2H), 3.0 (t, 2H,J=7 Hz). IR (KBr, cm⁻¹) 3265, 1707.8, 1585.2, 1505, 1496.2, 1487.2,1408.7, 1268.1, 1233.5, 845.65, 754. MS(ES⁺) m/e 397 [M+H]⁺. MS(ES⁻) m/e395 [M−H]⁻. Anal. Calcd. for C₂₀H₂₀N₄O₃S C, 60.59; H, 5.08; N, 14.13.Found C, 60.23; H, 5.08; N, 13.66. Analytical LC/MS 100% purity (diodearray detector). M.P.=108–181° C.

f)1-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-imidazolidin-2-one

A DMF suspension of1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-imidazolidin-2-one(0.76 g, 1.92 mmol, 1 eq.) and 1-(chloroethyl)pyrrolidine hydrochloride(0.34 g, 2.02 mmol, 1.05 eq.) was treated with NaH (0.16 g, 60% in oil,4.03 mmol, 2.1 eq.) and the reaction heated to 85° C. overnight. Thereaction was diluted with EtOAc and washed with water. The organic layerwas collected, dried over MgSO₄, and the solvent removed leaving anorange/brown oil that was purified by normal phase chromatography usinga step gradient of 2M NH3 in MeOH in chloroform as the mobile phaseleaving a yellow oil which produced1-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-imidazolidin-2-one(0.28 g, 29% yield) as a yellow solid on trituration with ether.

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.77 (d, 2H, J=9 Hz), 7.27 (m,2H), 6.93 (m, 3H), 4.19 (m, 4H), 3.87 (m, 2H), 3.56 (m, 2H), 3.32 (m,6H), 3.02 (t, 2H, J=7 Hz), 2.6 (bt, 2H), 1.68 (m, 4H). IR (KBr, cm⁴′)3403.8, 2948.7, 2922.6, 2769.3, 1688.4, 1613.2, 1507.1, 1485.9, 1424.2,1268, 1242, 740.5. MS(ES⁺) m/e 494 [M+H]⁺. Analytical LC/MS 100% (diodearray and light scattering detection). M.P.=125–129° C.

Example 258 Preparation ofN,N-dimethyl-M-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-ethane-1,2-diamine

a) 6-Chloro-nicotinic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

The above compound was prepared in a similar manner to that exemplifiedfor the preparation of Example 101c from 2-chloropyridine-5-carboxylicacid (Aldrich, 2.0 g, 12.69 mmol, 1 eq.),(2-phenoxy-ethylsulfanyl)-acetic acid hydrazide (Maybridge, 2.87 g,12.69 mmol, 1 eq.), and EEDQ (3.45 g, 13.96 mmol, 1.1 eq.). The reactionwas worked up as described and the brown oil purified by silica gelchromatography using a step gradient of EtOAc in hexanes as the mobilephase. Removal of the solvent in vacuo left 6-chloro-nicotinic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (3.95 g, 85% yield) asa white solid.

¹HNMR (DMSO-d6) δ 10.76 (s, 1H), 10.26 (s, 1H), 8.87 (m, 1H), 8.26 (m,1H), 7.69 (d, 1H, J=8 Hz), 7.29 (m, 2H), 6.95 (m, 3H), 4.2 (t, 2H, J=7Hz), 3.35 (s, 2H), 3.04 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3222.8, 1605.3,1493, 1459.5, 1253.7, 1174.2, 1110.4, 1035.5, 756.3, 599.8. MS(ES⁺) m/e366 [M+H]⁺, 272 [M−OPh]⁺. MS(ES⁻) m/e 364 [M−H]⁻. Analytical LC/MS 100%(diode array detection). M.P.=136–138° C.

b)2-Chloro-5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine

The above compound was prepared in a similar manner to that exemplifiedfor the preparation of Example 101d from 6-chloro-nicotinic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (3.48 g, 9.51 mmol, 1eq.). The crude material was purified by silica gel chromatography usinga step gradient of EtOAc in hexanes as the mobile phase. The solvent wasremoved in vacuo leaving2-chloro-5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine(2.50 g, 76% yield) as an off-white solid.

¹H NMR (DMSO-d6) δ 8.97 (m, 1H), 8.36 (m, 1H), 7.75 (d, 1H, J=8 Hz),7.26 (m, 2H), 6.92 (m, 3H), 4.25 (s, 2H), 4.19 (t, 2H, J=6 Hz), 3.04 (t,2H, J=6 Hz). IR (KBr, cm⁻¹) 2924, 1602.7, 1570.5, 1499, 1465.5, 1385,1248.7, 1176.5, 1136.6, 1114.2, 1035.7, 1004.6, 843.9, 750.5. MS(ES⁻)346 [M−H]⁻. Analytical LC/MS 100% (diode array detection). M.P.=113–115°C.

c)N,N-Dimethyl-M-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-ethane-1,2-diamine

2-Chloro-5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine(0.72 g, 2.07 mmol, 1 eq.) was suspended in N,N-dimethylethylenediamine(5 mL) and the reaction heated to 100° C. for three hours. The reactionwas diluted with EtOAc and washed two times with water and then brine.The organic layer was collected, dried over MgSO₄, filtered, and thesolvent removed in vacuo leaving an orange oil that was purified bysilica gel chromatography using 10% 2M NH₃ in MeOH in Et₂O as the mobilephase. Removal of the solvent in vacuo left and orange oil which wastriturated with diethyl ether producingN,N-dimethyl-M-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-ethane-1,2-diamine(0.28 g, 34% yield) as an off-white solid.

¹H NMR (DMSO-d6) δ 8.54 (m, 1H), 7.82 (m, 1H), 7.27 (m, 3H), 6.93 (m,3H), 6.64 (d, 1H, J=9 Hz), 4.17 (m, 4H), 3.41 (m, 2H), 3.01 (t, 2H, J=7Hz), 2.42 (t, 2H, J=7 Hz), 2.18 (s, 6H). IR (CHCl₃, cm⁻¹) 3388.1,3007.6, 2864.4, 2825.5, 2777.3, 1612.7, 1498.6, 1406.2, 1343.1, 1299.4,1224.9, 1173.2, 1144.7, 1034.3, 957.4, 823.5. MS(ES⁺) m/e 400 [M+H]⁺.MS(ES⁻) m/e 398 [M−H]⁻. Analytical LC/MS 100% purity (diode arraydetection). M.P.=97–98° C.

Example 259N,N-Dimethyl-N′-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-propane-1,3-diamine

The above compound was prepared in a similar manner to that exemplifiedfor the preparation of Example 258 from2-chloro-5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine(0.75 g, 2.16 mmol, 1 eq.) and 3-dimethylaminopropylamine (6 mL).Purification and trituration as described leftN,N-dimethyl-N-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-propane-1,3-diamine(0.31 g, 35% yield) as a white solid.

¹H NMR (DMSO-d6) δ 8.54 (m, 1H), 7.82 (m, 1H), 7.39 (m, 1H), 7.27 (m,2H), 6.93 (m, 3H), 6.58 (d, 1H, J=9 Hz), 4.17 (m, 4H), 3.33 (m, 2H),3.01 (t, 2H, J=7 Hz), 2.27 (t, 2H, J=7 Hz), 2.13 (s, 6H), 1.67 (m, 2H).IR (CHCl₃, cm⁻¹) 3007.1, 2949.9, 2864.7, 2824.4, 1613.1, 1498.5, 1411.8,1344.5, 1299, 1243.4, 1223.4, 1173.1, 1145.4, 1081.8, 1034.6. MS (ES⁺)m/e 414 [M+H]⁺. MS (ES⁻) m/e 412 [M−H]⁻. Anal. Calcd. for C₂₁H₂₇N₅O₂S C,60.99; H, 6.58; N, 16.93. Found C, 60.94; H, 6.61; N, 16.60. AnalyticalLC/MS 100% purity (diode array detection). M.P.=94–96° C.

Example 260 Preparation of1-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-piperidin-4-one

Prepared in a similar manner as 68b from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.350 g, 0.864 mM), piperidin-4-one, trifluoroacetic acid (0.921 g,4.32 mM), NaI (0.065 g, 0.432 mM), and NaHCO₃ (0.399 g, 0.475 mM) in 3mL DMF. The mixture was heated to 950 overnight in a sealed tube andworked up to give 0.304 g brown oil which was purified by columnchromatography to give 0.139 g of material which was combined withanother lot and repurified on normal phase chromatography with 50:50ethyl acetate:dichloromethane with 1% 2M ammonia in methanol to give0.097 g (19%) of the title compound

¹H NMR (DMSO-d6) δ 7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H,J=9 Hz), 6.9 (m, 3H), 4.2 (m, 6H), 3.0 (t, 2H, J=6 Hz), 2.7 (m, 4H), 2.6(t, 2H, J=7 Hz), 2.3 (m, 4H), 1.9 (m, 2H). IR (KBr, cm⁻¹) 2930, 1704,1613, 1499, 1392, 1303, 1249, 1170, 1083, 1031, 847, 758, 694. MS (ESI)m/e 468.3, 500.3. Anal. Calcd for C₂₅H₂₉N₃O₄S₁: C, 64.22; H, 6.25; N,8.98. Found C, 64.10; H, 6.27; N, 8.92. M.P.=55–57° C.

Example 261 Preparation ofdiisopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine

Prepared in a similar manner as 68b from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.477 g, 1.2 mM), diisopropylamine (8.66 g. 86 mM), NaI (0.088 g, 0.59mM), and NaHCO₃ (0.297 g, 3.54 mM) in 3 mL DMF. The solution was heatedto 95° overnight in a sealed tube and worked up to give 0.417 g brownoil, which was purified by column chromatography as in 68b andrecrystallized from ethyl ether and ethyl acetate to give 0.266 g (48%)of the title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (m, 2H), 3.0 (m, 4H), 2.6 (m, 2H), 1.8 (m, 2H),0.9 (m, 12H). IR (KBr, cm⁻¹) 2965, 1616, 1501, 1265, 1242, 1176, 751. MS(ESI) m/e 470. Anal. Calcd for C₂₆H₃₅N₃O₃S₁: C, 66.49; H, 7.51; N, 8.95.Found C, 66.08; H, 7.57; N, 8.76. M.P.=30–33° C. HPLC 100%.

Example 262 Preparation ofdiisopropyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine

Prepared in a similar manner as 68b from2-[4-(4-chloro-butoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.458 g, 1.09 mM), diisopropylamine (8.00 g. 79 mM), NaI (0.082 g, 0.55mM), and NaHCO₃ (0.275 g, 3.27 mM) in 5 mL DMF. The solution was heatedto 95° overnight in a sealed tube. Chromatography gave 0.238 g (45%) ofdiisopropyl-(4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyl)-amine.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 4H), 4.1 (m, 2H), 3.0 (m, 4H), 2.4 (m, 2H), 1.7 (m, 2H),1.5 (m, 2H), 0.9 (m, 12H). IR (KBr, cm⁻¹) 1615, 1504, 1255, 1174, 833.MS (ESI) m/e 484. Anal. Calcd for C₂₇H₃₇N₃O₃S₁: C, 67.05; H, 7.71; N,8.68. Found C, 66.20; H, 7.53; N, 8.57. M.P.=42–44° C. HPLC 100%.

Example 263 Preparation of2-[4-(3-azetidin-1-yl-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

Prepared in a similar manner as 68b from2-[4-(3-chloro-propoxy)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.348 g, 0.86 mM), azetidine, monohydrochloride, (0.402 g, 4.3 mM), NaI(0.064 g, 0.43 mM), NaHCO₃ (0.433 g, 5.15 mM) in 3 mL DMF. The solutionwas heated to 95° overnight in a sealed tube. Chromatography andrecrystallization from ethyl ether and ethyl acetate gave 30 mg (8%) ofthe title compound.

¹H NMR (CDCl₃-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (m, 2H), 7.0 (m, 3), 6.9 (d, 2H, J=8 Hz), 4.2(t, 2H, J=6 Hz), 4.0 (m, 4H), 3.2 (t, 4H, J=7 Hz), 3.0 (t, 2H, J=6 Hz),2.6 (t, 2H, J=7 Hz), 2.1 (m, 2H), 1.9 (m, 2H). IR (KBr, cm⁻¹) 2926,1622, 1603, 1499, 1250, 753. MS (ESI) m/e 426. M.P.=60° C. HPLC 100%.

Example 264 Preparation of4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-butyronitrile

A solution of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.435 g, 1.32 mM), K₂CO₃ (0.492 g, 3.56 mM) and 4-chlorobutyronitrile(0.293 g, 1.98 mM) was heated to 70° in 10 mL DMF for 4 hrs. Theresultant mixture was extracted 2 times with ethyl acetate and washedwith water, brine, dried over sodium sulfate and concentrated to give0.452 g crude product. The mixture was purified directly by columnchromatography on silica gel (elution with 1/1 ethyl acetate, toluenefollowed by chloroform/2 m ammonia in methanol to give 0.378 g (72%) ofthe title compound.

¹H NMR (DMSO-d6)

7.9 (d, 2H, J=9 Hz), 7.2 (t, 2H, J=8 Hz), 7.1 (d, 2H, J=9 Hz), 6.9 (m,3H), 4.2 (m, 6H), 3.0 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=7 Hz), 2.0 (m, 2H).IR (KBr, cm⁻¹) 2930, 1610, 1499, 1464, 1425, 1303, 1253, 1179, 1051,842, 755. MS (ESI) m/e 396. Anal. Calcd for C₂₁H₂₁N₃O₃S₁: C, 63.78; H,5.35; N, 10.62. Found C, 60.25; H, 5.13; N, 9.89. M.P.=67–68° C. HPLC93%.

Example 265 Preparation of1-(2-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-ethyl)-azepane

Prepared in a similar manner as 66c from4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol (0.461 g, 1.41mM) and 1-(2-chloro-ethyl)-azepane, monohydrochloride (0.419 g, 2.11 mMto give 0.196 g (31%) of the title compound.

¹H NMR (DMSO-d6)

7.6 (d, 2H, J=9 Hz), 7.4 (s, 1H), 7.2 (t, 2H, J=8 Hz), 7.0 (d, 2H, J=9Hz), 6.9 (m, 3H), 4.1 (t, 2H, J=7 Hz), 4.0 (m, 4H), 3.0 (t, 2H, J=6 Hz),2.8 (m, 2H), 2.7 (m, 4H), 1.5 (m, 8H). IR (KBr, cm⁻¹) 2924, 2822, 1604,1550, 1502, 1465, 1299, 1251, 1173, 1106, 1029, 818, 750. MS (ESI m/e453. Anal. Calcd for C₂₆H₃₂N₂O₃S₁: C, 68.99; H, 7.13; N, 6.19. Found C,68.84; H, 7.03; N, 6.21. M.P.=35–38° C. HPLC 100%.

Example 266 Preparation of1-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azepane

54a)5-[4-(3-Chloro-propoxy)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole

Prepared in a similar manner as 68a from4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenol (1.186 g, 3.62mM) and 1-bromo-3-chloro-propane (0.855 g, 5.43 mM) to give 0.904 g(62%) of5-[4-(3-chloro-propoxy)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole.

¹H NMR (DMSO-d6)

7.6 (d, 2H, J=9 Hz), 7.4 (s, 1H), 7.2 (t, 2H, J=8 Hz), 7.0 (d, 2H, J=9Hz), 6.9 (m, 3H), 4.1 (m, 4H), 4.0 (s, 2H), 3.8 (t, 2H, J=6 Hz), 3.0 (t,2H, J=6 Hz), 2.2 (m, 2H). IR (KBr, cm⁻¹) 2972, 2922, 1603, 1506, 1466,1295, 1243, 1175, 1105, 1031, 943, 834, 805, 761. MS (ESI) m/e 404.Anal. Calcd for C₂₁H₂₂C₁₁N₁O₃S₁: C, 62.44; H, 5.49; N, 3.47. Found C,60.66; H, 5.24; N, 3.39. M.P.=71–73° C. HPLC 100%.

54b)1-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azepane

Prepared in a similar manner as 68b from5-[4-(3-chloro-propoxy)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole(0.400 g, 0.99 mM), azepane (2.45 g, 24.7 mM), NaI (0.074 g, 0.495 mM),and NaHCO₃ (0.22 g, 2.77 mM) in 3 mL DMF. The solution was heated to 90°overnight in a sealed tube. Chromatography and recrystallization fromhexane and ethyl ether gave 0.178 g (38%) of the title compound.

¹H NMR (DMSO-d6)

7.6 (d, 2H, J=9 Hz), 7.4 (s, 1H), 7.2 (t, 2H, J=8 Hz), 7.0 (d, 2H, J=9Hz), 6.9 (m, 3H), 4.1 (t, 2H, J=7 Hz), 4.0 (m, 4H), 3.0 (t, 2H, J=6 Hz),2.6 (m, 6H), 1.8 (m, 2H), 1.5 (m, 8H). IR (KBr, cm⁻¹) 2923, 2850, 1602,1551, 1507, 1465, 1255, 1176, 1110, 1033, 941, 832, 751, 691. MS (ESI)m/e 467. Anal. Calcd for C₂₇H₃₄N₂O₃S₁: C, 69.49; H, 7.34; N, 6.00. FoundC, 69.78; H, 7.43; N, 4.09. M.P.=32–35° C. HPLC 100%.

Example 267 Preparation of1-(3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azocaneoxalic acid salt

Prepared in a similar manner as 68b from5-[4-(3-chloro-propoxy)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole(0.488 g, 1.21 mM), azocane (3.42 g, 30 mM), NaI (0.091 g, 0.495 mM),and NaHCO₃ (0.28 g, 3.39 mM) in 3 mL DMF. The solution was heated to 90°overnight in a sealed tube. Chromatography was followed by formation ofthe oxalic acid salt. The product mixture was dissolved in acetone (3mL) and to that was added dropwise a solution of oxalic acid (0.063 g,0.7 mM) in acetone (2 mL). The mixture was concentrated to low volumeand to this was added ethyl ether (5 mL). Upon cooling, a solidprecipitated and was collected by filtration and dried under vacuum(40°) to give 0.194 g (28%) of the title compound.

¹H NMR (DMSO-d6)

7.6 (d, 2H, J=9 Hz), 7.4 (s, 1H), 7.2 (m, 2H), 7.0 (d, 2H, J=9 Hz), 6.9(m, 3H), 4.2 (t, 2H, J=7 Hz), 4.1 (t, 2H, J=6 Hz), 4.0 (s, 2H) 3.0 (t,2H, J=6 Hz), 2.1 (m, 2H), 1.5–1.9 (m, 10H). IR (KBr, cm⁻¹) 2934, 1717,1601, 1506, 1245, 1203, 1035, 836, 759, 705. MS (ESI) m/e 481. Anal.Calcd for C₃₀H₃₈N₂O₇S₁: C, 63.14; H, 6.71; N, 4.91. Found C, 60.25; H,6.40; N, 4.64. M.P.=89–94° C. HPLC 80%.

Example 268 Preparation of2-(2-phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propenyl)-phenyl]-oxazole

a) (2-Thiocyanato-ethoxy)-benzene

A solution of (2-bromo-ethoxy)-benzene (18.0 g, 89.5 mM) and KSCN (26.1g, 268 mM) were added together in a nitrogen flushed round bottom flask.The mixture was heated for 3 hours at 100° C., followed by dilution withH₂O (300 mL), and extraction twice with EtOAc. The combined organicextracts were washed with H₂O (10×100 mL), brine (2×100 mL)), dried oversodium sulfate and concentrated to dryness to give 12.8 g (yellow oil)(80%) of the title compound.

¹H NMR (DMSO-d6)

7.3 (t, 2H, J=8 Hz), 6.9 (m, 3H), 4.3 (t, 2H, J=5 Hz), 3.5 (t, 2H, J=5Hz). IR (CHCl₃, cm⁻¹) 3669, 3520, 3016, 2923, 2870, 2158, 1670, 1601,1497, 1465, 1385, 1303, 1236, 1083, 1038. MS (ESI) m/e 179. Anal calcd.C₉H₉NOS: C, 60.31; H, 5.06; N, 7.81. Found C, 60.11; H, 5.06; N, 7.53.HPLC 100%.

b) Dimer of 2-phenoxy-ethanethiol

To a solution of (2-thiocyanato-ethoxy)-benzene (12.8 g, 71.4 mM) inMeOH (200 mL) was added a dropwise solution of NaOMe (70 mL, 321 mM, 25%NaOMe in MeOH) over 25 min. The reaction mixture was stirred for 2.5hours. The mixture was then filtered and the collected solid was driedunder vacuum overnight to give a white solid, 7.9 g (72%)

¹H NMR (DMSO-d6) δ 7.3 (t, 2H, J=8 Hz), 6.9 (m, 3H), 4.2 (t, 2H, J=6Hz), 3.1 (m, 2H). IR (CHCl₃, cm⁻¹) 1600, 1587, 1497, 1243, 1225, 1173,1032, 1016. MS (ESI) m/e 306. Anal. Calcd for C₁₆H₁₈O₂S₂: C, 62.71; H,5.92; N, 0.00. Found C, 61.28; H, 5.76; N, 0.72. M.P.=72–75° C. HPLC100%.

c) 2-Phenoxy-ethanethiol

A solution of the dimer of 2-phenoxy-ethanethiol (6.3 g, 20.4 mM) and Zndust (12 g, 184 mM) was refluxed in acetic acid (120 mL) for 2 hours.The mixture was diluted with H₂O (300 mL), extracted withdichloromethane, dried over sodium sulfate, filtered and concentrated todryness to give 5.2 g (83%) of 2-phenoxy-ethanethiol.

¹H NMR (DMSO-d6)

7.3 (t, 2H, J=8 Hz), 6.9 (m, 3H), 4.0 (t, 2H, J=6 Hz), 2.8 (m, 2H).

d) N-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-2-chloro-acetamide

A CH₂Cl₂ suspension (100 mL) of 4-bromophenacylamine hydrochloride (10g, 39.92 mmol, 1 eq.) and chloroacetyl chloride (6.76 g, 59.88 mmol, 1.5eq.) was treated with 100 mL of triethylamine (12.12 g, 119.76 mmol, 3eq.) in CH₂Cl₂ dropwise over 1.5 hours. After addition had ceased, thereaction was allowed to stir overnight at room temperature.

The reaction was washed with 0.1 M aqueous HCl and then brine. Theorganic layer was collected, dried over MgSO₄, filtered, and the solventremoved in vacuo leaving a dark brown oil which was purified via normalphase chromatography using a step gradient of EtOAc in hexanes as themobile phase giving 8.38 g (72% yield) of a yellow solid.

¹H NMR (DMSO-d6) δ 8.56 (t, 1H, J=5 Hz), 7.93 (d, 2H, J=8 Hz), 7.76 (d,2H, J=8 Hz), 4.66 (m, 2H), 4.20 (s, 2H). IR (CHCl₃, cm⁻¹) 3397, 3009,1672, 1590, 1526, 1074, 987. MS (ES⁺) m/z 290, 292 [M+H]⁺. MS (ES⁻) m/z288, 290 [M−H]⁻. Anal. Calcd for C₁₀H₉BrClNO₂: C, 41.34; H, 3.12; N,4.82. Found C, 41.23; H, 2.95; N, 4.75. M.P.=145–146° C.

e) 5-(4-Bromo-phenyl)-2-chloromethyl-oxazole

A POCl₃ suspension (70 mL) ofN-[2-(4-bromo-phenyl)-2-oxo-ethyl]-2-chloro-acetamide (7.38 g, 25.4mmol, 1 eq) was refluxed for 2 hours. The cooled solution was pouredinto ice and stirred for several hours. The aqueous layer was extractedwith EtOAc. The organic layer was collected, dried over MgSO₄, filtered,and the solvent removed in vacuo leaving a dark brown oil which waspurified by normal phase chromatography using a gradient of EtOAc inhexanes as the mobile phase leaving5-(4-bromo-phenyl)-2-chloromethyl-oxazole (5.85 g, 85% yield) as a lightbrown solid.

¹H (DMSO-d6) δ 7.8 (s, 1H), 7.7 (m, 4H), 4.9 (s, 2H). IR (CHCl₃, cm⁻¹)3005, 1481, 1405, 1216, 1119, 1074, 1011, 823. MS (ES⁺) m/z 272, 274[M+H]⁺. Anal. calcd. for C₁₀H₇BrClNO C, 44.07; H, 2.59; N, 5.14. FoundC, 44.06; H, 2.41; N, 5.04.

f) 5-(4-Bromo-phenyl)-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole

A solution of 2-phenoxy-ethanethiol (3.3 g, 21.39 mmol, 1 eq.) and5-(4-bromo-phenyl)-2-chloromethyl-oxazole (5.83 g, 21.39 mmol, 1 eq.) inanhydrous DMF was treated with solid potassium carbonate (8.87 g, 64.17mmol, 3 eq.) and allowed to stir overnight. Diluted the reaction withwater and extracted 2×250 mL with EtOAc. The organic layers werecombined, washed with 50% brine, collected, dried over MgSO₄, filtered,and the solvent removed in vacuo leaving a tan solid which was purifiedby normal phase chromatography using a step gradient of EtOAc in hexanesas the mobile phase leaving 8.16 g (98% yield) of a tan solid.

¹H NMR (DMSO-d6) δ 7.65 (m, 5H), 7.27 (m, 2H), 6.93 (m, 3H), 4.16 (t,2H, J=7 Hz), 4.06 (s, 2H), 3.00 (t, 2H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3009,2930, 2871, 1601, 1497, 1481, 1243, 1073, 822. MS (ES⁺) m/z 390, 392[M+H]⁺. Anal. Calcd. for C₁₈H₁₆BrNO₂S C, 55.39; H, 4.13; N, 3.59. FoundC, 55.31; H, 4.03; N, 3.60. M.P.=82–84° C.

g) 3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-acrylicacid ethyl ester

To a closed reaction vessel was added5-(4-bromo-phenyl)-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole (1.372 g,3.52 mM), triethylamine (0.427 g, 4.22 mM), Hartwig's ligand¹ (0.126 g,0.178 mM), bis(dibenzylideneacetone)palladium (0.051 g, 0.088 mM), andethyl acrylate (0.49 g, 4.93 mM) in DMF (5 mL). The mixture was heatedovernight at 80° C., filtered through celite, and concentrated to lowvolume. The crude reaction mixture was diluted with ethyl acetate andwater and separated. The aqueous mixture was extracted with ethylacetate and the organic extracts combined, which were then washed withwater, brine, dried over sodium sulfate, and concentrated to dryness.The residue was purified directly by column chromatography on silica gel(elution with 20% ethyl acetate/hexane followed by 30% ethylacetate/hexane to give 1.097 g (76%) 55 g.

¹H NMR (DMSO-d6)

7.8 (d, 2H, J=8 Hz), 7.7–7.6 (m, 4H), 7.3 (t, 2H, J=8 Hz), 6.9 (m, 3H),6.7 (d, 1H, J=16 Hz), 4.2 (m, 4H), 4.1 (s, 2H), 3.0 (t, 2H, J=7 Hz), 1.3(t, 3H, J=7 Hz). MS (ESI) m/e 409.8. Anal. Calcd for C₂₃H₂₃N₁O₄S₁: C,67.46; H, 5.66; N, 3.42. Found C, 66.03; H, 5.54; N, 3.28. M.P.=65–67°C. HPLC 100%.

h) 3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl)-acrylicacid

A solution of3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-acrylicacid ethyl ester (2.323 g (5.67 mM), in 1N NaOH (12 mL, 11.9 mM), EtOH(19 mL), and THF (20 mL) was stirred overnight at room temperature. Thereaction mixture was concentrated to low volume and diluted with ethylacetate/H₂O. The aqueous material was acidified with 1N HCl andextracted with ethyl acetate (4×100 mL). The combined organic extractswere washed with brine, dried over sodium sulfate and concentrated todryness to give 1.082 g (50%) of3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-acrylicacid

¹H NMR (DMSO-d6)

7.3 (t, 2H, J=8 Hz), 6.9 (m, 3H), 4.2 (t, 2H, J=6 Hz), 3.1 (m, 2H). IR(KBr, cm⁻¹) 3437, 2928, 1681, 1604, 1499, 1422, 1258, 1220, 1171, 829,747. MS (ESI) m/e 382. Anal. Calcd for C₂₁H₁₉NO₄S₁: C, 66.12; H, 5.02;N, 3.67. Found C, 65.99; H, 5.21; N, 3.35. M.P.=150–153° C. HPLC 100%.

i) ii)3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-prop-2-en-1-ol

A solution of3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-acrylicacid (1.9 g, 4.98 mM), diethyl chlorophosphate, (1.031 g, 5.98 mM), andtriethylamine (1.0 g, 9.96 mM was stirred at room temperature in THF(155 mL) for 22 hours. The mixture was filtered, washed with THF, andthe filtrate concentrated to dryness. The filtrate was redissolved in120 mL THF and to this mixture was added dropwise over 3 min. a solutionof NaBH₄ (0.378 g, 9.96 mM) dissolved in H₂O (5 mL) and THF (20 mL).After stirring at room temperature for 2.5 hours, 1N HCl (10 mL) wasadded dropwise and the mixture was stirred overnight at roomtemperature. The mixture was concentrated to low volume, diluted withethyl acetate, washed with water, 1N HCl, water, sodium bicarbonate,water, brine, dried over sodium sulfate, and concentrated to dryness.The residue was purified directly by column chromatography (elution withethyl acetate/toluene followed by 95% chloroform/5% 2M ammonia inmethanol) to give 0.331 g (18%) of3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-prop-2-en-1-ol.

¹H NMR (DMSO-d6)

7.6 (d, 3H, J=8 Hz), 7.5 (d, 2H, J=8 Hz), 7.2 (t, 2H, J=8 Hz), 6.9 (m,3H), 6.5 (d, 1H, J=16 Hz), 6.4 (tt, 1H, J=5 Hz), 4.2 (m, 4H), 4.0 (s,2H), 3.0 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3431, 2916, 1653, 1601, 1496,1247, 968, 750. MS (ESI) m/e 368. Anal. Calcd for C₂₁H₂₁NO₃S₁: C, 68.64;H, 5.76; N, 3.81. Found C, 64.83; H, 5.36; N, 3.57. M.P.=73–74° C.

j)5-[4-(3-Bromo-propenyl)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole

To a solution of triphenylphosphine (0.247 g, 0.943 mM) dissolved indichloromethane (3 mL) was added bromine (0.151 g, 0.0943 mM) dropwiseand the mixture was stirred for 10 min at room temperature. The mixturewas cooled to +5° C. and a solution of3-{4-[2-(2-phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-prop-2-en-1-ol(0.333 g, 0.898 mM) and imidazole (0.122 g, 1.8 mM) in dichloromethane(5 mL) was added dropwise. The mixture was stirred at room temperaturefor 3 hours and washed with water, sodium bicarbonate, water, brine,dried over sodium sulfate and concentrated to dryness. The residue waspurified directly by column chromatography on silica gel (elution with1/3 ethyl acetate/hexane followed by ethyl acetate/tolune to give 0.165g (43%) of5-[4-(3-bromo-propenyl)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole.

¹H NMR (DMSO-d6)

7.6 (d, 3H, J=7 Hz), 7.5 (d, 2H, J=8 Hz), 7.3 (t, 2H, J=8 Hz), 6.9 (m,3H), 6.8 (d, 1H, J=16 Hz), 6.6 (m, 1H), 4.4 (d, 2H, J=8 Hz), 4.2 (t, 2H,J=6 Hz), 4.0 (s, 2H), 3.0 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3447, 2923,2862, 1601, 1546, 1491, 1468, 1241, 1204, 1106, 1033, 965, 944, 821,764, 694, 519. MS (S]) m/e 432. Anal. Calcd for C₂₁H₂₀BrNO₂S₁: C, 58.61;H, 4.68; N, 3.25. Found C, 59.30; H, 5.03; N, 3.05. M.P.=88–91° C.

k)2-(2-phenoxy-ethylsulfanylmethyl)-5-[4-(3-pyrrolidin-1-yl-propenyl)-phenyl]-oxazole

Prepared in a similar manner as 68b from5-[4-(3-bromo-propenyl)-phenyl]-2-(2-phenoxy-ethylsulfanylmethyl)-oxazole(0.150 g, 0.348 mM), pyrrolidine (1.73 g, 24.4 mM), NaI (0.026 g, 0.174mM), and NaHCO₃ (0.088 g, 1.04 mM) in 3 mL DMF. Chromatography andrecrystallization from ethyl ether and hexane gave 0.044 g (30%) of thetitle compound.

¹H NMR (DMSO-d6)

7.6 (d, 3H, J=7 Hz), 7.5 (d, 2H, J=8 Hz), 7.2 (t, 2H, J=8 Hz), 6.9 (m,3H), 6.6 (d, 1H, J=16 Hz), 6.4 (m, 1H), 4.2 (t, 2H, J=7 Hz), 4.1 (s,2H), 3.2 (d, 2H, J=7 Hz), 3.0 (t, 2H, J=7 Hz), 1.7 (m, 4H). IR (KBr,cm⁻¹) 2957, 2912, 2778, 1604, 1501, 1463, 1255, 1107, 1056, 973, 944,822, 754, 693. MS (ESI) m/e 421. Anal. Calcd for C₂₅H₂₈N₂O₂S₁: C, 71.40;H, 6.71; N, 6.66. Found C, 70.88; H, 6.68; N, 6.57. M.P.=73–75° C.

Example 269 Preparation ofDimethyl-(3-{4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

a) 4-Hydroxy-benzoic acid N′-[2-(4-phenoxy-phenyl)-acetyl]-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 4-phenoxyphenylacetic acid(1.16 g, 5.0 mM) to afford 1.59 g (87%) of 4-Hydroxy-benzoic acidN′-[2-(4-phenoxy-phenyl)-acetyl]-hydrazide as a white solid (MP 181–183°C., MW 362.39).

¹H NMR DMSO-d6) δ 10.04 (m, 3H), 7.72 (d, 2H, J=8 Hz), 7.35 (d, 2H, J=8Hz), 7.33 (d, 2H, J=9 Hz), 7.11 (t, 1H, J=8 Hz), 6.96 (m, 4H), 6.79 (d,2H, J=9 Hz), and 3.50 (s, 2H). IR (KBr, cm⁻¹) 3292, 1607, 1576, 1510,1490, 1311, 1279, 1245, 1172, 848, 755, 693, and 507. MS (ESI) m/e 363,361. Anal. Calcd for C₂₁H₁₈N₂O₄: C, 69.60; H, 5.01; N, 7.73. Found C,69.08; H, 4.99; N, 7.73.

b) 4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenol

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from 4-Hydroxy-benzoic acidN′-[2-(4-phenoxy-phenyl)-acetyl]-hydrazide (1.53 g, 4.22 mM),triphenylphosphine (2.24 g, 8.44 mM, and triethylamine (2.12 mL, 15.19mM) to afford 0.835 g (57%) of4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenol as a white solid(MP 202–203° C., MW 344.37).

¹H NMR (DMSO-d6) δ 10.24 (s, 1H), 7.77 (d, 2H, J=9 Hz), 7.37 (m, 4H),7.12 (t, 1H, J=7 Hz), 6.98 (m, 4H), 6.91 (d, 2H, J=9 Hz), and 4.29 (s,2H). IR (KBr, cm⁻¹) 3124, 2803, 1889, 1610, 1500, 1426, 1366, 1284,1250, 1172, 1083, 1021, 857, 816, 780, 735, and 691. MS (ESI) m/e 345,343. Anal. Calcd for C₂₁H₁₆N₂O₃: C, 73.24; H, 4.68; N, 8.13. Found C,73.08; H, 4.86; N, 8.06.

c)Dimethyl-(3-{4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt

A solution of 4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenol(0.344 g, 1.0 mM), 3-chloro-N,N-dimethylpropylamine hydrochloride (0.174g, 1.1 mM), and Triton B (40 weight % in CH₃OH, 1.05 mL, 2.3 mM) in 5 mLDMF was stirred at 50–90° C. for 5.5 h. Cesium carbonate (0.066 g, 0.2mM, 0.4 eq) was then added, and the reaction mixture heated at 90° C.for an additional 4.5 h. The reaction mixture was allowed to cool toroom temperature and diluted with ethyl acetate/H₂O. The solvent layerswere separated, the aqueous layer back extracted with ethyl acetate, thecombined organic extracts washed with water, saturated NaHCO₃ solution,1N NaOH, and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford 0.297 g (69%) of a gold gum.Purification by Chromatotron radial chromatography on silica gel(isocratic elution with 95:5 CH₂Cl₂/2.0 M ammonia in methanol) afforded0.147 g (34%) ofDimethyl-(3-{4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amineas a colorless gum. The gum (0.143 g, 0.33 mM) was dissolved in 2 mLacetone, and oxalic acid (0.033 g, 0.36 mM), dissolved in 1 mL acetone,was added with rapid stirring at room temperature followed by theaddition of diethyl ether/hexane (1:2, 3 mL). Filtered the resultantthick precipitate, washed the collected solid with diethyl ether andhexane, and dried in vacuo at 40° C. to afford 0.167 g (97%) ofDimethyl-(3-{4-[5-(4-phenoxy-benzyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-amine,oxalic acid salt as a white solid (MP 156–158° C., MW oxalate salt519.56, MW free amine 429.21).

¹H NMR DMSO-d6) δ 7.89 (d, 2H, J=9 Hz), 7.38 (d, 2H, J=8 Hz), 7.36 (d,2H, J=9 Hz), 7.12 (t, 1H, J=8 Hz), 7.11 (d, 2H, J=9 Hz), 6.99 (d, 2H,J=8 Hz), 6.98 (d, 2H, J=9 Hz), 4.31 (s, 2H), 4.12 (t, 2H, J=6 Hz), 3.15(t, 2H, J=7 Hz), 2.74 (s, 6H), and 2.09 (m, 2H). IR (KBr, cm⁻¹) 3435,3034, 2931, 2659, 2562, 1722, 1612, 1589, 1496, 1475, 1428, 1309, 1256,1169, 1053, 961, 872, 841, 739, 692, and 482. MS (ESI) m/e 430. Anal.Calcd for C₂₆H₂₇N₃O₃—C₂H₂O₄: C, 64.73; H, 5.63; N, 8.09. Found C, 64.11;H, 5.68; N, 7.80. Analytical HPLC: 100% purity.

Example 270 Preparation of1-{3-[4-(5-Benzofuran-2-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-piperidine

a) 4-(3-Piperidin-1-yl-propoxy)-benzoic acidN′-(2-benzofuran-2-yl-acetyl)-hydrazide

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 51a, from 2-benzofurylacetic acid (0.529g, 3.0 mM) and 4-(3-piperidin-1-yl-propoxy)-benzoic acid hydrazide(0.749 g, 3.0 mM) followed by purification by column and Chromatotronradial chromatography on silica gel (isocratic elution with 95:5CH₂Cl₂/2.0 M ammonia in methanol) to afford 0.437 g (33%) of4-(3-Piperidin-1-yl-propoxy)-benzoic acidN′-(2-benzofuran-2-yl-acetyl)-hydrazide as an off-white solid (MW435.53).

¹H NMR (DMSO-d₆) δ 10.28 (s, 1H), 10.21 (s, 1H), 7.83 (d, 2H, J=9 Hz),7.57 (d, 1H, J=8 Hz), 7.50 (d, 1H, J=8 Hz), 7.22 (m, 2H), 6.99 (d, 2H,J=9 Hz), 6.78 (s, 1H), 4.04 (t, 2H, J=6 Hz), 3.80 (s, 2H), 2.36 (t, 2H,J=7 Hz), 2.31 (m, 4H), 1.86 (m, 2H), 1.47 (m, 4H), and 1.36 (m, 2H). IR(KBr, cm⁻¹) 3234, 2933, 1646, 1606, 1500, 1453, 1304, 1252, 1175, and750. MS (ESI) m/e 436, 434. Anal. Calcd for C₂₅H₂₉N₃O₄: C, 68.95; H,6.71; N, 9.65. Found C, 67.82; H, 6.71; N, 9.59.

b)1-{3-[4-(5-Benzofuran-2-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-piperidine

The above compound was prepared in a manner similar to that exemplifiedfor the preparation of Example 49e, from4-(3-Piperidin-1-yl-propoxy)-benzoic acidN′-(2-benzofuran-2-yl-acetyl)-hydrazide (0.422 g, 0.97 mM),triphenylphosphine (0.514 g, 1.94 mM), and triethylamine (0.487 mL, 3.49mM) followed by column chromatography purification on silica gel(isocratic elution with ethyl acetate followed by 95:5 CH₂Cl₂/2.0 Mammonia in methanol) to afford 0.129 g (31%) of1-{3-[4-(5-Benzofuran-2-yl-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-propyl}-piperidineas a tan solid (MP 76–79° C., MW 417.51).

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=9 Hz), 7.53 (d, 1H, J=8 Hz), 7.45 (d,1H, J=8 Hz), 7.24 (m, 2H), 6.95 (d, 2H, J=9 Hz), 6.69 (s, 1H), 4.47 (s,2H), 4.15 (t, 2H, J=6 Hz), 3.09 (m, 2H), 2.47 (m, 2H), and 1.58 (m,10H). IR (KBr, cm⁻¹) 3439, 2935, 2852, 2806, 2767, 2633, 2545, 1614,1589, 1500, 1455, 1415, 1305, 1257, 1176, 1123, 1009, 955, 833, 739,523, and 435. MS (ESI) m/e 418, 416. Anal. Calcd for C₂₅H₂₇N₃O₃: C,71.92; H, 6.52; N, 10.06. Found C, 67.92; H, 6.28; N, 9.26. AnalyticalHPLC: 100% purity.

Example 271 Preparation of5-(2-Phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole

a) 4-Benzyloxy-N-(2,3-dihydroxy-propyl)-benzamide

A solution of 4-benzyloxy-benzoic acid (9.08 g, 39.8 mM) and(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine (4.97 g, 37.9 mM) in 75 mLmethylene chloride was treated with dicyclohexylcarbodiimide (8.21 g,39.8 mM) and stirred for 36 h at room temperature. After evaporation ofthe solvent in vacuo the remaining solid was dissolved in 250 mL acidicacid:water (4:1) and warmed to 50° C. for 6 h. The solvents wereevaporated and the remaining oil purified by chromatography on silicagel (elution with gradient ethyl acetate/ethanol) to afford a whitesolid as a mixture of 4-benzyloxy-N-(2,3-dihydroxy-propyl)-benzamide anddicyclohexyl urea. The latter crystallized out of 40 mL ethanol at 5° C.After evaporation of the solvent 4.0 g(33%)4-benzyloxy-N-(2,3-dihydroxy-propyl)-benzamide was obtained as anoil.

¹H NMR (DMSO-d₆, 300 MHz) δ 8.23 (t, J=5 Hz, 1H), 7.83 (t, J=8 Hz, 2H),7.49–7.30 (m, 5H), 7.07 (t, J=8 Hz, 2H), 5.18 (s, 2H), 4.80 (br s, 1H),4.65 (br s, 1H), 3.68–3.53 (m, 1H), 3.42–3.12 (m, 4H). MS (ESI): m/e=302(MH)⁺.

b) 4-Methoxy-benzoic acid 3-(4-benzyloxy-benzoylamino)-2-hydroxy-propylester

A solution of 4-benzyloxy-N-(2,3-dihydroxy-propyl)-benzamide (4.0 g,13.27 mM) and triethylamine (4.02 g, 39.82 mM) in 150 mL methylenechloride was cooled to 5° C. and treated with a solution of4-methoxy-benzoic acid chloride (2.26 g, 13.27 mM) in 50 mL methylenechloride. Within 14 h the reaction mixture was allowed to warm to roomtemperature and was than quenched with 150 mL water. The organic layerwas washed with 10 mL 2M hydrochloric acid, dried over sodium sulfateand evaporated. The remaining oil was purified by chromatography onsilica gel (elution with gradient methylene chloride/ethanol) to afford2.2 g (38%) 4-methoxy-benzoic acid3-(4-benzyloxy-benzoylamino)-2-hydroxy-propyl ester as a white solid.

¹H NMR (DMSO-d₆, 300 MHz) δ 8.38 (t, J=5 Hz, 1H), 7.96 (t, J=8 Hz, 2H),7.83 (t, J=8 Hz, 2H), 7.49–7.28 (m, 5H), 7.10–7.02 (m, 4H), 5.26 (br s,1H), 5.18 (s, 2H), 4.25–3.95 (m, 3H), 3.85 (s, 3H), 3.40–3.25 (m, 2H).MS (ESI): m/e=436 (MH)⁺.

c) 4-Methoxy-benzoic acid 3-(4-benzyloxy-benzoylamino)-2-oxo-propylester

A solution of 4-methoxy-benzoic acid3-(4-benzyloxy-benzoylamino)-2-hydroxy-propyl ester (1.2 g, 2.76 mM) in30 mL methylene chloride was cooled to 5° C. and treated with 7.8 mL ofa solution of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one inmethylene chloride (Dess-Martin reagent, 15 wt % in methylene chloride,from Acros). After 2 h the reaction mixture was allowed to warm to roomtemperature and the solvent was removed in vacuo. The remains werevigorously stirred with 50 mL of ethyl acetate/tert-butylmethyl ether(5:1) and filtered. The solution was washed with 20 mL water, dried oversodium sulfate and evaporated to afford 1.0 g (84%) 4-methoxy-benzoicacid 3-(4-benzyloxy-benzoylamino)-2-oxo-propyl ester as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.06 (t, J=8 Hz, 2H), 7.82 (t, J=8 Hz, 2H),7.47–7.28 (m, 5H), 7.02 (t, J=8 Hz, 2H), 6.96 (t, J=8 Hz, 2H), 6.82 (brs, 1H), 5.18 (s, 2H), 5.00 (s, 2H), 4.52 (s, 2H), 3.88 (s, 3H). MS (ES):m/e=434 (MH)⁺.

d) 4-Methoxy-benzoic acid 2-(4-benzyloxy-phenyl)-oxazol-5-ylmethyl ester

A solution of 4-methoxy-benzoic acid3-(4-benzyloxy-benzoylamino)-2-oxo-propyl ester (1.0 g, 2.3 mM) in 150mL anhydrous dioxane in an Argon atmosphere was treated with(methoxycarbonylsulfamoyl)-triethylammonium hydroxide (1.1 g, 4.6 mM) inone portion and heated to 68° C. for 30 minutes. The reaction mixturewas poured into 50 mL of water and extracted with 70 mL ethyl acetate.

The organic layer was dried over sodium sulfate and evaporated. Theremaining oil was purified by chromatography on silica gel (elution withgradient ethyl acetate/hexane) to afford 320 mg (31%) 4-methoxy-benzoicacid 2-(4-benzyloxy-phenyl)-oxazol-5-ylmethyl ester as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.01 (t, J=9 Hz, 2H), 7.98 (t, J=9 Hz, 2H),7.47–7.33 (m, 5H), 7.23 (s, 1H), 7.05 (t, J=8 Hz, 2H), 6.92 (t, J=8 Hz,2H), 5.28 (s, 2H), 5.15 (s, 2H), 3.88 (s, 3H). MS (ESI): m/e=416 (MH)⁺.

e) 4-Methoxy-benzoic acid 2-(4-hydroxy-phenyl)-oxazol-5-ylmethyl ester

A solution of 4-methoxy-benzoic acid2-(4-benzyloxy-phenyl)-oxazol-5-ylmethyl ester (320 mg, 7.7 mM) inmethanol was filled in an autoclave and treated with 10% Palladium oncharcoal (32 mg, 3.0·10⁻⁵ M). The autoclave was charged with hydrogen (8bar) and the reaction mixture stirred at 50° C. of 6 h. The pressure wasreleased and the suspension filtered and evaporated to afford 226 mg(90%) of 4-methoxy-benzoic acid 2-(4-hydroxy-phenyl)-oxazol-5-ylmethylester as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.02 (t, J=9 Hz, 2H), 7.93 (t, J=9 Hz, 2H),7.25 (s, 1H), 6.94–6.87 (m, 4H), 5.38 (s, 2H), 3.88 (s, 3H). MS (ESI):m/e=326 (MH)⁺.

f) 4-Methoxy-benzoic acid2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-ylmethyl ester

A suspension of 4-methoxy-benzoic acid2-(4-hydroxy-phenyl)-oxazol-5-ylmethyl ester (220 mg, 0.68 mM),N-(2-chloro-ethyl)-pyrrolidine hydrochloride (115 mg, 0.68 mM), andpotassium carbonate (929 mg, 6.72 mM) in 20 mL dimethylformamide washeated at 60° C. for 3 h. The solvent was removed in vacuo and theremains partitioned between 10 mL water and 30 mL methylene chloride.The organic layer was dried over sodium sulfate and evaporated. Theremaining oil was purified by chromatography on silica gel (elution withgradient methylene chloride/ethanol containing 10% ammonia) to afford100 mg (35%) of 4-methoxy-benzoic acid2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-ylmethyl ester s awhite solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.97–7.82 (m, 4H), 7.15 (s, 1H), 6.94–6.82 (m,4H), 5.38 (s, 2H), 4.39 (t, J=6 Hz, 2H), 3.88 (s, 3H), 2.85 (t, J=6 Hz,2H), 2.63–2.52 (m, 4H), 1.80–1.70 (m, 4H). MS (ESI): m/e=423(MH)⁺.

g) {2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-yl}-methanol

A solution of 4-methoxy-benzoic acid2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-ylmethyl ester (95 mg,0.23 mM) in anhydrous tetrahydrofuran was treated with lithium aluminiumhydride (2 mg, 5.6×10⁻⁵ M) at 5° C. and stirred for 30 minutes. Thereaction was quenched with 0.2 mL acetone and evaporated. The remainingoil was dissolved in 75 mL methylene chloride and washed with 50 mLwater. The organic layer was dried over sodium sulfate and evaporatedand the remaining oil purified by chromatography on silica gel (elutionwith gradient methylene chloride/ethanol containing 10% ammonia) toafford 15 g (23%) of{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-yl}-methanol as awhite solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.99 (d, J=9 Hz, 2H), 7.12 (s, 1H), 6.98 (d,J=9 Hz, 2H), 4.75 (s, 2H), 4.45 (t, J=6 Hz, 2H), 4.00–3.90 (m, 2H), 3.55(t, J=6 Hz, 2H), 3.05–2.90 (m, 2H), 2.20–2.10 (m, 4H). MS (ESI): m/e=289(MH)⁺.

h)5-(2-Phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole

A solutuion of{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazol-5-yl}-methanol (6.5 mg,2.26×10⁻⁵ M) and triethylamine (8.2 mg, 8.11×10⁻⁵ M) in 2 mL methylenechloride was cooled to 5° C., treated with methane sulfonyl chloride(2.8 mg, 2.48×10⁻⁵ M) in 1 mL methylene chloride and stirred for 30minutes.

In a separate flask 3 mL ethanol were treated with sodium hydride (8.2mg, 0.34 mM) at 5° C., stirred for 10 minutes before2-phenoxy-ethanethiol (50.2 mg, 0.325 mM) was added. This solution wasstirred for further 10 minutes at 5° before it was added to the firstsolution at 5° C. Stirring of the combined solutions was continued for72 h. The solvent was evaporated in vacuo and the remains were pouredinto 10 mL water. The aqueous phase was extracted twice with 10 mLmethylene chloride. The organic layer was dried over sodium sulfate andevaporated and the remaining oil purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol containing 10%ammonia) to afford 1.5 mg (16%) of5-(2-phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazoleas a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.93 (d, J=9 Hz, 2H), 7.30–7.27 (m, 2H),7.01–6.88 (m, 6H), 4.25–4.14 (m, 4H), 3.95 (s, 2H), 2.98–2.89 (m, 4H),2.72–2.60 (m, 4H), 1.88–1.78 (m, 4H). MS (ESI): m/e=425 (MH)⁺.

Example 272 Preparation of4-Methyl-5-(2-phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole

a) 2-(4-Methoxy-benzoylamino)-propionic acid methyl ester

A solution of 4-methoxy-benzoic acid (5.20 g, 34.2 mM) in 35 mLdimethylformamide was cooled to 0° C. and treated with N,N′-carbonyldi-imidazole (5.55 g, 34.2 mM). Stirring was continued for 30 minutesbefore L-alanine methyl ester hydrochloride (4.68 g, 33.5 mM) was added.The reaction mixture was allowed to warm to room temperature and stirredfor 16 h. The solvent was removed in vacuo and the remaining oil pouredinto 200 mL of 2N HCl and extracted twice with 30 mL methylene chloride.The organic layer was washed twice with 50 mL 5% aqueous Na₂CO₃solution, dried over sodium sulfate and evaporated to afford 4.28 g(53%) of 2-(4-methoxy-benzoylamino)-propionic acid methyl ester as awhite solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.78 (d, J=9 Hz, 2H), 6.94 (d, J=9 Hz, 2H),6.67 (br s, 1H), 4.80 (q, J=8 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 1.55(d, J=8 Hz, 3H). MS (ESI): m/e=238 (MH)⁺.

b) 2-(4-Methoxy-benzoylamino)-propionic acid

A solution of 2-(4-methoxy-benzoylamino)-propionic acid methyl ester(4.20 g, 17.7 mM) in 20 mL tetrahydrofuran and water (1:1) was treatedwith lithium hydroxide (0.43 g, 35 mM) and stirred for 20 h at roomtemperature. The reaction mixture was diluted with 2N HCl until a pH=1was reached. The precipitation was filtered and dried to afford 2.5 g(63%) 2-(4-methoxy-benzoylamino)-propionic acid as a white solid.

¹H NMR (DMSO-d₆, 300 MHz) δ 12.50 (br s, 1H), 8.48 (d, J=7 Hz, 1H), 7.88(d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 4.42 (q, J=8 Hz, 1H), 3.82 (s,3H), 1.45 (d, J=8 Hz, 3H). MS (ESI): m/e=224 (MH)⁺.

c) 2-(4-Methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid methyl ester

A suspension of 2-(4-methoxy-benzoylamino)-propionic acid (1.8 g, 8.0mM) in 32 mL benzene and 120 mL methylene chloride was treated withoxalyl chloride (10 g, 80 mM) and stirred for 18 h at room temperature.During that time, the suspension turned into a solution. The volatileswere removed in vacuo, the remaining oil was cooled to 0° C. and treatedwith triethylamine (1.2 g, 12 mM) followed by addition of 60 mL methanoland stirred for 2 h at room temperature. The solvents were removed invacuo. The remains were extracted with tert-butyl methyl ether. Theether layer was evaporated and the remaining oil was purified bychromatography on silica gel with methylene chloride to afford 0.82 g(42%) 2-(4-methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid methylester as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.07 (d, J=9 Hz, 2H), 6.98 (d, J=9 Hz, 2H),3.95 (s, 3H), 3.87 (s, 3H), 2.55 (s, 3H),). MS (ESI): m/e=248 (MH)⁺.

d) [2-(4-Methoxy-phenyl)-4-methyl-oxazol-5-yl]-methanol

A solution of 4-(4-methoxy-phenyl)-4-methyl-oxazole-2-carboxylic acidmethyl ester (0.79 g, 3.19 mM) in 40 mL toluene was cooled to 0° C. andtreated with 7.9 mL di-isobutyl aluminium hydride solution (20% intoluene, 9.58 mM) and stirred for 2 h. The reaction mixture was allowedto warm to room temperature quenched with 5 mL methanol and evaporated.The remaining oil was dissolved in 15 mL methanol and filtered. Themethanolic layer was evaporated and the remaining oil purified bychromatography on silica gel (elution with gradient methylenechloride/ethanol) to afford 0.29 g (42%)[2-(4-methoxy-phenyl)-4-methyl-oxazol-5-yl]-methanol as a solid.

¹H NMR (DMSO-d₆, 300 MHz) δ 7.88 (d, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H),5.28 (t, J=7 Hz, 1H), 4.50 (d, J=7 Hz, 2H), 3.95 (s, 3H), 2.25 (s, 3).MS (ESI): m/e=220 (MH)⁺.

e) 2-(4-Methoxy-phenyl)-4-methyl-oxazole-5-carbaldehyde

A solution of [2-(4-methoxy-phenyl)-4-methyl-oxazol-5-yl]-methanol (0.18g, 0.79 mM) in 3 mL methylene chloride was cooled to 5° C. and treatedwith 2.5 g of a solution of1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one in methylenechloride (Dess-Martin reagent in solution, 15 wt %, from Acros). After2.5 h the reaction mixture was allowed to warm to room temperature andthe solvent was removed in vacuo. The remains were vigorously stirredwith 50 mL tert-butylmethyl ether and filtered. The solution was washedwith 10 mL water, dried over sodium sulfate and evaporated to afford0.16 g (92%) 2-(4-methoxy-phenyl)-4-methyl-oxazole-5-carbaldehyde as anoil.

¹H NMR (CDCl₃, 300 MHz) δ 9.88 (s, 1H), 8.10 (d, J=9 Hz, 2H), 7.00 (d,J=9 Hz, 2H), 3.90 (s, 3H), 2.58 (s, 3H). MS (ESI): m/e=218 (MH)⁺.

f) 2-(4-Hydroxy-phenyl)-4-methyl-oxazole-5-carbaldehyde

2-(4-Methoxy-phenyl)-4-methyl-oxazole-5-carbaldehyde (0.16 g, 0.73 mM)was dissolved in 4 mL methylene chloride, cooled to −20° C. and treatedwith 2.58 mL 1M boron tribromide solution in methylene chloride. Within2 h the reaction mixture was allowed to warm to room temperature andstirred for 28 h. The reaction mixture was quenched with 3 mL water. Theorganic layer was dried over sodium sulfate and evaporated. Theremaining was oil purified by chromatography on silica gel (elution withgradient methylene chloride/ethanol) to afford 63 mg (42%)2-(4-hydroxy-phenyl)-4-methyl-oxazole-5-carbaldehyde as a white solid.

¹HNMR (CDCl₃, 300 MHz) δ 9.85 (s, 1H), 8.06 (d, J=9 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 2.60 (s, 3H). MS (ESI): m/e=204 (M)⁺.

g) Acetic acid 4-(5-formyl-4-methyl-oxazol-2-yl)-phenyl ester

A solution of 2-(4-hydroxy-phenyl)-4-methyl-oxazole-5-carbaldehyde (63mg, 0.31 mM) in 1 mL tetrahydrofuran was treated with triethylamine(31.5 mg, 0.31 nM) and acetyl chloride (24.5 mg, 0.31 mM) and stirred atroom temperature for 2 h. The solvent was evaporated and the remainsdissolved in 4 mL methylene chloride and 4 mL water. The organic layerwas dried over sodium sulfate and evaporated to afford 56 mg (74%)aceticacid 4-(5-formyl-4-methyl-oxazol-2-yl)-phenyl ester as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 9.85 (s, 1H), 8.18 (d, J=9 Hz, 2H), 7.27 (d,J=9 Hz, 2H), 2.58 (s, 3H), 2.35 (s, 3H). MS (ESI): m/e=246 (MH)⁺.

h) Acetic acid 4-(5-hydroxymethyl-4-methyl-oxazol-2-yl)-phenyl ester

A solution of acetic acid 4-(5-formyl-4-methyl-oxazol-2-yl)-phenyl ester(56 mg, 0.23 mM) in 5 mL methanol and water (4:1) was treated withsodium borohydride (0.33 mg, 8.6×10⁻⁵ M) at 0° C. and stirred for 30minutes. The reaction was quenched with 0.2 mL acetone and evaporated.The remaining oil was dissolved in 7 mL methylene chloride and washedwith 5 mL water. The organic layer was dried over sodium sulfate andevaporated and the remaining oil purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol) to afford 31.5 mg(55%) acetic acid 4-(5-hydroxymethyl-4-methyl-oxazol-2-yl)-phenyl esteras a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.05 (d, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 2H),4.70 (s, 2H), 2.48 (s, 3H), 2.27 (s, 3H). MS (ESI): m/e=248 (MH)⁺.

i) 4-[4-Methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol

A solution of acetic acid4-(5-hydroxymethyl-4-methyl-oxazol-2-yl)-phenyl ester (120 mg, 0.49 mm)and triethylamine (54 mg, 0.53 mM) in 2 mL methylene chloride was cooledto 5° C., treated with methane sulfonyl chloride (61 mg, 0.53 mM) in 1mL methylene chloride and stirred for 30 minutes.

In a separate second flask 8 mL ethanol were treated with sodium hydride(42 mg, 1.75 mM) at 5° C., stirred for 10 minutes before2-phenoxy-ethanethiol (270 mg, 1.75 mM) was added. This solution wasstirred for further 10 minutes at 5° before the two separate solutionswere combined at that temperature through addition of second solution tothe first one. Stirring of the combined solutions was continued for 72h. The solvent was evaporated in vacuo and the remains were poured into10 mL water. The aqueous phase was extracted with methylene chloride.The organic layer was dried over sodium sulfate and evaporated and theremaining oil purified by chromatography on silica gel (elution withgradient methylene chloride/ethanol) to afford 96 mg (53%)4-[4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol as awhite solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.83 (d, J=9 Hz, 2H), 7.32–7.22 (m, 2H9,7.00–6.80 (m, 5H), 4.20 (t, J=7 Hz, 2H), 3.92 (s, 2H), 2.92 (t, J=7 Hz,2H), 2.27 (s, 3H). MS (ESI): m/e=342 (MH)⁺.

j)4-Methyl-5-(2-phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazole

A suspension of4-[4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol (57mg, 0.17 mM), N-(2-chloro-ethyl)-pyrrolidine hydrochloride (31 mg, 0.18mM), and potassium carbonate (51 mg, 0.37 mM) in S mL dimethylformamidewas heated at 80° C. for 16 h. The solvent was removed in vacuo and theremains partitioned between 2 mL water and 5 mL methylene chloride. Theorganic layer was dried over sodium sulfate and evaporated. Theremaining oil was purified by chromatography on silica gel (elution withgradient methylene chloride/ethanol containing 10% ammonia) to afford 39mg (53%)4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-oxazoleas a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.93 (d, J=9 Hz, 2H), 7.33–7.25 (m, 2H),7.01–6.88 (m, 5H), 4.25–4.10 (m, 4H), 3.95 (s, 2H), 2.98–2.89 (m, 4H),2.70–2.55 (m, 4H), 2.23 (s, 3H), 1.88–1.77 (m, 4H). MS (ESI): m/e=439(MH)⁺.

Example 273 Preparation ofDimethyl-(3-{4-[4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenoxy}-propyl)-amine

A suspension of4-[4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenol (26mg, 0.08 mM), (3-chloro-propyl)-dimethyl-amine hydrochloride (13.2 mg,0.08 mM), and potassium carbonate (23 mg, 0.17 mM) in 5 mLdimethylformamide was heated at 80° C. for 16 h. The solvent was removedin vacuo and the remains partitioned between 2 mL water and 5 mLmethylene chloride. The organic layer was dried over sodium sulfate andevaporated. The remaining oil was purified by chromatography on silicagel (elution with gradient methylene chloride/ethanol containing 10%ammonia) to afford 17 mg (52%)dimethyl-(3-{4-[4-methyl-5-(2-phenoxy-ethylsulfanylmethyl)-oxazol-2-yl]-phenoxy}-propyl)-amineas a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 7.91 (d, J=9 Hz, 2H), 7.33–7.24 (m, 2H),7.00–6.87 (m, 5H), 4.20 (t, J=7 Hz, 2H), 4.08 (t, J=7 Hz, 2H), 3.92 (s,2H), 2.95 (t, J=7 Hz, 2H), 2.48 (t, J=7 Hz, 2H), 2.28 (s, 6H), 2.22 (s,3H), 2.02–1.92 (m, 2H). MS (ESI): m/e=428 (MH)³⁰.

Example 274 Preparation of[3-(4-{5-[2-(4-trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) Methyl 4-(3-dimethylamino-propoxy)-benzoate

To a cold mixture (0° C.) of methyl 4-hydroxybenzoate (33.93 g, 223mmol), triphenylphosphine (53.29 g, 203 mmol), and3-dimethylaminopropanol-1 (20.88 g, 202 mmol) in anhydrous THF (180 mL)was added diisopropylazodicarboxylate (44 mL, 223 mmol) over 5 minuteswith stirring. The stirring continued at 0° C. for 30 minutes and then23° C. overnight. After removal of solvent, the residue was submitted toa flash filtration chromatography on silica gel (elution with ethylacetate, then 20% 2M NH₃-MeOH in CH₂Cl₂). A yellowish oil was obtained(44.83 g, 94%).

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.85 Hz), 6.88 (d, 2H, J=8.85 Hz), 4.04(t, 2H, J=6.55 Hz), 3.85 (s, 3H), 2.42 (t, 2H, J=7.26 Hz), 2.22 (s, 6H),1.94 (m, 2H, J=6.55, 7.26 Hz). MS (ES⁺) m/e 238.

b) 4-(3-Dimethylamino-propoxy)-benzoic hydrazide

A mixture of methyl 4-(3-dimethylamino-propoxy)-benzoate (44.83 g, 189mmol) and hydrazine monohydrate (100 g, 2000 mmol) was stirred at 80° C.overnight; then it was allowed to cool to 23° C. A white solid formed.The solid was collected by filtration, washed with hexanes (3×50 mL),and dried in vacuum to afford a white powder (32.01 g, 71%).

¹H NMR (CDCl₃) δ 7.67 (d, 2H, J=8.85 Hz), 6.90 (d, 2H, J=8.85 Hz), 7.36(s, b, 1H), 4.02 (t, 2H, J=6.37 Hz), 4.00 (s, b, 2H), 2.42 (t, 2H,J=7.26 Hz), 2.22 (s, 6H), 1.93 (m, 2H, J=6.37, 7.26 Hz). MS (ES⁺) m/e238. mp 79.5–81.0° C. Anal. Calcd for C₁₂H₁₉N₃O₂: C, 60.74; H, 8.07; N,17.71. Found C, 60.39; H, 7.97; N, 17.63.

c) Ethylene glycol mono-p-toluate

To a cold solution (0° C.) of triethylamine (40 mL, 287 mmol) andethylene glycol (60 mL, 1080 mol) in dichloromethane (300 mL) was addedp-toluoyl chloride (27 mL, 200 mmol) with stirring. After 30 minutes,cooling bath was removed and stirring continued overnight at 23° C. Thereaction mixture was distributed between diethyl ether (300 mL) andwater (300 mL). The organic phase was isolated and washed subsequentlywith 0.3 N HCl (aq, 200 mL), sat. NaHCO₃ (aq, 200 mL), and sat. NaCl(aq, 200 mL). After removal of solvent, the residue was purified on asilica gel column with hexanes-ethyl acetate (3:1) to give a white solid(29.34 g, 81.4%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.49 Hz), 7.22 (d, 2H, J=7.78 Hz),4.41–4.45 (m, 2H), 3.94 (q, 2H, J=5.83, 9.37 Hz), 2.39 (s, 3H), 2.03 (t,2H, J=5.83 Hz). MS (ES⁺) m/e 181. mp 44.5–45.0° C.

d) 2-(4-Trifluoromethoxy-phenoxy)-ethyl p-toluate

To a cold mixture (0° C.) of ethylene glycol mono-p-toluate (1.80 g, 10mmol), triphenylphosphine (2.88 g, 11 mmol), and 4-trifuoromethoxyphenol(1.87 g, 10.5 mmol) in anhydrous THF (10 mL) was addeddiisopropylazodicarboxylate (2.2 mL, 10.5 mmol) with stirring. Thereaction mixture was stirred at 0° C. for 30 minutes and then 23° C.overnight. After removal of solvent, the residue was purified bychromatography on silica gel (elution with 5% ethyl acetate in hexanes)to provide a white solid (3.06 g, 90%).

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=8.14 Hz), 7.21 (d, 2H, J=8.14 Hz), 7.13(d, 2H, J=8.85 Hz), 6.91 (d, 2H, J=8.85 Hz), 4.63 (t, 2H, J=4.77 Hz),4.27 (t, 2H, J=4.77 Hz), 2.38 (s, 3H). MS (ES⁺) m/e 341. mp 76.0–77.5°C.

e) 2-(4-Trifluoromethoxy-phenoxy)-ethanol-1

A solution of 2-(4-trifluoromethoxy-phenoxy)-ethyl p-toluate (3.06 g, 9mmol) in 2 N LiOH (20 mL, 40 mmol), THF (15 mL), and MeOH (15 mL) wasstirred at 23° C. overnight. After neutralized with sat. NaHCO₃ (aq, 100mL), the reaction mixture was extracted with diethyl ether (3×100 mL).The combined organic phases were dried over anhydrous sodium sulfate.After removal of solvent, a colorless oil was obtained (2.00 g, 100%)

¹H NMR (CDCl₃) δ 7.13 (d, 2H, J=9.20 Hz), 6.89 (d, 2H, J=9.20 Hz), 4.05(t, 2H, J=4.42 Hz), 3.95 (m, b, 2H), 1.96 (t, b, 1H). MS (ES⁺) m/e 223.

f) 2-(4-Trifluoromethoxy-phenoxy)-ethyl tosylate

A cold solution of 2-(4-trifluoromethoxy)-ethanol-1 (667 mg, 3 mmol),pyridine (0.5 mL, 6 mmol), and p-toluenesulfonyl chloride (860 mg, 4.5mmol) in chloroform (5 mL) was stirred at 0° C. After 6 hours, solventwas removed and the residue was submitted to a silica gel chromatography(elution with 20% ethyl acetate in hexanes) to afford a white solid (858mg, 76%).

¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.14 Hz), 7.31 (d, 2H, J=8.14 Hz), 7.08(d, 2H, J=9.20 Hz), 6.75 (d, 2H, J=9.20 Hz), 4.34–4.38 (m, 2H),4.10–4.14 (m, 2H), 2.42 (s, 3H). MS (ES⁺) m/e 377. mp 35.0–36.0° C.

g) Methyl 2-(4-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate

A mixture of 2-(4-trifluoromethoxy-phenoxy)-ethyl tosylate (753 mg, 2mmol), methyl thioglycolate (0.4 mL, 7 mmol), and potassium carbonate(875 mg, 6 mmol) in THF (5 mL) was stirred at 65° C. overnight. Thereaction mixture was filtered and washed with diethyl ether (3×6 mL) anddichloromethane (2×6 mL). After evaporation of solvent, the residue waspurified by chromatography on silica gel (elution with 20% ethyl acetatein hexanes) to deliver a colorless oil (619 mg, 100%).

¹H NMR (CDCl₃) δ 7.12 (d, 2H, J=9.20 Hz), 6.86 (d, 2H, J=9.20 Hz), 4.15(t, 2H, J=6.37 Hz), 3.71 (s, 3H), 3.33 (s, 2H), 3.01 (t, 2H, J=6.37 Hz).MS (ES⁺) m/e 311.

h) 2-(4-Trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid

A solution of methyl2-(4-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate (619 mg, 2.0 mmol)in 2 N LiOH (aq, 3 mL), MeOH (3 mL), and THF (3 mL) was stirred at 23°C. After one hour, the reaction mixture was acidified with 3 N HCl (aq,4 mL). The aqueous layer was isolated and extracted twice withdichloromethane (25 mL each). The combined organic phases were driedwith anhydrous magnesium sulfate. After removal of solvent, a colorlessoil was obtained (580 mg, 98%).

¹H NMR (CDCl₃) δ 7.12 (d, 2H, J=9.20 Hz), 6.86 (d, 2H, J=9.20 Hz), 4.17(t, 2H, J=6.01 Hz), 3.37 (s, 2H), 3.03 (t, 2H, J=6.01 Hz). MS (ES⁻) m/e295.

i)[3-(4-{5-[2-(4-Trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

To a cold solution (0° C.) of2-(4-trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid (296 mg, 1mmol), 4-(3-dimethylamino-propoxy)-benzoic hydrazide (237 mg, 1 mmol),and triphenylphosphine (1.31 g, 5 mmol) in anhydrous acetonitrile (10mL) was added a mixture of carbon tetrachloride (0.58 mL, 6 mmol) andtriethylamine (0.97 mL, 7 mmol) with stirring. The stirring continued at0° C. for 30 minutes and then 23° C. overnight. After evaporation ofsolvent, the residue was distributed between 1N NaOH (30 mL) anddichloromethane (25 mL). The aqueous layer was isolated and extractedtwice with dichloromethane (25 mL each). The combined organic phaseswere dried with anhydrous sodium sulfate. After removal of solvent, theresidue was submitted for purification on silica gel (elution with ethylacetate, then 4% 2 M NH₃—MeOH in dichloromethane) to yield a white solid(267 mg, 54%).

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.85 Hz), 7.09 (d, 2H, J=8.86 Hz), 6.97(d, 2H, J=8.85 Hz), 6.85 (d, 2H, J=8.86 Hz), 4.15 (t, 2H, J=6.19 Hz),4.07 (t, 2H, J=6.37 Hz), 4.00 (s, 2H), 3.02 (t, 2H, J=6.19 Hz), 2.45 (t,2H, J=7.08 Hz), 2.24 (s, 6H), 1.97 (m, 2H, J=6.37, 7.08 Hz). MS (ES⁺)m/e 498. mp 92.5–93.5° C. Anal. Calcd for C₂₃H₂₆F₃N₃O₄S: C, 55.52; H,5.27; N, 8.45; S, 6.44; F, 11.46. Found C, 55.29; H, 5.14; N, 8.38; S,6.28; F, 11.38.

Example 275 Preparation of[3-(4-{5-[2-(2-trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) 2-(2-Trifluoromethoxy-phenoxy)-ethyl p-toluate

In a similar manner as exemplified in Example 274 part d),2-trifluoromethoxy-phenol (1.87 g, 10.5 mmol) was converted into2-(2-trifluoromethoxy-phenoxy)-ethyl p-toluate (3.10 g, 87%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=8.14 Hz), 7.17–7.26 (m, 4H), 7.02 (dd,1H, J=1.42, 8.85 Hz), 6.95 (td, 1H, J=1.42, 7.78 Hz), 4.65 (t, 2H,J=4.78 Hz), 4.34 (t, 2H, J=4.78 Hz), 2.38 (s, 3H). MS (ES⁺) m/e 341.

b) 2-(2-Trifluoromethoxy-phenoxy)-ethanol-1

In a similar manner as exemplified in Example 274 part e),2-(2-trifluoromethoxy-phenoxy)-ethyl p-toluate (2.72 g, 8 mmol) wasconverted into 2-(2-trifluoromethoxy-phenoxy)-ethanol-1 (1.74 g, 98%) asa colorless oil.

¹H NMR (CDCl₃) δ 7.20–7.27 (m, 2H), 7.69–7.02 (m, 2H), 4.12 (t, 2H,J=4.42 Hz), 3.96 (q, 2H, J=4.95, 9.20), 2.06 (m, b, 1H). MS (ES⁺) m/e223.

c) 2-(2-Trifluoromethoxy-phenoxy)-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-(2-trifluoromethoxy-phenoxy)-ethanol-1 (666 mg, 2 mmol) was convertedinto 2-(2-trifluoromethoxy-phenoxy)-ethyl tosylate (926 mg, 82%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.14 Hz), 7.31 (d, 2H, J=8.14 Hz),7.16–7.22 (m, 2H), 6.95 (t, 1H, J=7.78 Hz), 6.90 (d, 1H, J=7.78 Hz),4.32–4.36 (m, 2H), 4.18–4.23 (m, 2H), 2.42 (s, 3H). MS (ES⁺) m/e 377.

d) Methyl 2-(2-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g),2-(2-trifluoromethoxy-phenoxy)-ethyl tosylate (753 mg, 2 mmol) wasconverted into methyl2-(2-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate (620 mg, 100%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.18–7.25 (m, 2H), 6.89–7.00 (m, 2H), 4.22 (t, 2H,J=6.37 Hz), 3.71 (s, 3H), 3.39 (s, 2H), 3.04 (t, 2H, J=6.37 Hz). MS(ES⁺) m/e 311.

e) 2-(2-Trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(2-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate (620 mg, 2 mmol)was converted into 2-(2-trifluoromethoxy-phenoxy)-ethylsulfanyl aceticacid (592 mg, 100%) as a white solid.

¹H NMR (CDCl₃) δ 7.18–7.26 (m, 2H), 6.92–6.99 (m, 2H), 4.24 (t, 2H,J=6.01 Hz), 3.44 (s, 2H), 3.07 (t, 2H, J=6.01 Hz). MS (ES³¹ ) m/e 295.mp 41.5–42.5° C.

f)[3-(4-{5-[2-(2-Trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-(2-trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid (296 mg, 1mmol) was converted into[3-(4-{5-[2-(2-trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine(320 mg, 64%) as a white solid.

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=9.20 Hz), 7.18–7.25 (m, 2H), 6.97 (d,2H, J=9.20 Hz), 6.91–6.96 (m, 2H), 4.24 (t, 2H, J=6.19 Hz), 4.07 (t, 2H,J=6.55 Hz), 4.05 (s, 2H), 3.07 (t, 2H, J=6.19 Hz), 2.45 (t, 2H, J=7.08Hz), 2.25 (s, 6H), 1.97 (m, 2H, J=6.55, 7.08 Hz). MS (ES⁺) m/e 498. mp55.0–55.5° C. Anal. Calcd for C₂₃H₂₆F₃N₃O₄S: C, 55.52; H, 5.27; N, 8.45;S, 6.44; F, 11.46. Found C, 55.28; H, 5.32; N, 8.26; S, 6.48; F, 11.76.

Example 276 Preparation of[3-(4-{5-[2-(3-trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) 2-(3-Trifluoromethoxy-phenoxy)-ethyl p-toluate

In a similar manner as exemplified in Example 274 part d),3-trifluoromethoxy-phenol (1.87 g, 10.5 mmol) was converted into2-(3-trifluoromethoxy-phenoxy)-ethyl p-toluate (3.31 g, 93%) as a whitesolid.

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.14 Hz), 7.27 (t, 1H, J=8.32 Hz), 7.22(d, 2H, J=8.14 Hz), 6.77–6.87 (m, 3H), 4.63 (t, 2H, J=4.77 Hz), 4.28 (t,2H, J=4.77 Hz), 2.39 (s, 3H). MS (ES⁺) m/e 341. mp 63.0–64.0° C.

b) 2-(3-Trifluoromethoxy-phenoxy)-ethanol-1

In a similar manner as exemplified in Example 274 part e),2-(3-trifluoromethoxy-phenoxy)-ethyl p-toluate (2.72 g, 8 mmol) wasconverted into 2-(3-trifluoromethoxy-phenoxy)-ethanol-1 (1.78 g, 100%)as a colorless oil.

¹H NMR (CDCl₃) δ 7.13 (d, 2H, J=8.85 Hz), 6.85–6.94 (m, 2H), 4.05 (t,2H, J=4.42 Hz), 3.95 (s, b, 2H), 1.96 (s, b, 1H). MS (ES⁺) m/e 223.

c) 2-(3-Trifluoromethoxy-phenoxy)-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-(3-trifluoromethoxy-phenoxy)-ethanol-1 (666 mg, 2 mmol) was convertedinto 2-(3-trifluoromethoxy-phenoxy)-ethyl tosylate (1.00 g, 89%) as awhite solid.

¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.49 Hz), 7.82 (d, 2H, J=8.49 Hz), 7.23(t, 1H, J=8.49 Hz), 6.80 (d, 1H, J=8.49 Hz), 6.70 (d, 1H, J=8.49 Hz),6.58 (s, 1H), 4.34–4.38 (m, 2H), 4.10–4.14 (m, 2H), 2.42 (s, 31). MS(ES⁺) m/e 377. mp 58.5–59.5° C.

d) Methyl 2-(3-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g),2-(3-trifluoromethoxy-phenoxy)-ethyl tosylate (753 mg, 2 mmol) wasconverted into methyl2-(3-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate (625 mg, 100%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.26 (t, 1H, J=8.49 Hz), 6.80 (d, 2H, J=8.49 Hz), 6.73(s, 1H), 4.16 (t, 2H, J=6.37 Hz), 3.71 (s, 3H), 3.34 (s, 2H), 3.01 (t,2H, J=6.37 Hz). MS (ES) m/e 311.

e) 2-(3-Trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(3-trifluoromethoxy-phenoxy)-ethylsulfanyl-acetate (620 mg, 2 mmol)was converted into 2-(3-trifluoromethoxy-phenoxy)-ethylsulfanyl aceticacid (513 mg, 87%) as a colorless oil.

¹H NMR (CDCl₃) δ 7.26 (t, 1H, J=8.14 Hz), 6.81 (d, 2H, J=8.14 Hz), 6.73(s, 1H), 4.18 (t, 2H, J=6.01 Hz), 3.38 (s, 2H), 3.04 (t, 2H, J=6.01 Hz).MS (ES) m/e 295.

f)[3-(4-{5-[2-(3-Trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-(3-trifluoromethoxy-phenoxy)-ethylsulfanyl acetic acid (296 mg, 1mmol) was converted into[3-(4-{5-[2-(3-trifluoromethoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine(280 mg, 56%) as a yellowish solid.

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.85 Hz), 7.24 (t, 1H, J=8.14 Hz), 6.97(d, 2H, J=8.85 Hz), 6.79 (d, 2H, J=8.14 Hz), 6.72 (s, 1H), 4.16 (t, 2H,J=6.02 Hz), 4.07 (t, 2H, J=6.37 Hz), 4.00 (s, 2H), 3.03 (t, 2H, J=6.02Hz), 2.45 (t, 2H, J=7.08 Hz), 2.25 (s, 6H), 1.97 (m, 2H, J=6.37, 7.08Hz). MS (ES⁺) m/e 498. mp 46.0–46.5° C. Anal. Calcd for C₂₃H₂₆F₃N₃O₄S:C, 55.52; H, 5.27; N, 8.45; S, 6.44; F, 11.46. Found C, 55.55; H, 5.18;N, 8.32; S, 6.49; F, 11.66.

Example 277 Preparation of[3-(4-{5-[2-(4-methoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) 2-(4-Methoxy-phenoxy)-ethyl p-toluate

In a similar manner as exemplified in Example 274 part d),4-methoxy-phenol (1.30 g, 10.5 mmol) was converted into2-(4-methoxy-phenoxy)-ethyl p-toluate (2.74 g, 91%) as a white solid.

¹HNMR (CDCl₃) δ 7.92 (d, 2H, J=8.14 Hz), 7.21 (d, 2H, J=8.14 Hz), 6.87(d, 2H, J=9.20 Hz), 6.81 (d, 2H, J=9.20 Hz), 4.60 (t, 2H, J=4.95 Hz),4.23 (t, 2H, J=4.95 Hz), 3.75 (s, 3H), 2.38 (s, 3H). MS (ES⁺) m/e 287.mp 40.5–42.5° C.

b) 2-(4-Methoxy-phenoxy)-ethanol-1

In a similar manner as exemplified in Example 274 part e),2-(4-methoxy-phenoxy)-ethyl p-toluate (2.29 g, 8 mmol) was convertedinto 2-(4-methoxy-phenoxy)-ethanol-1 (1.28 g, 95%) as a white solid.

¹H NMR (CDCl₃) δ 6.83 (m, 4H), 4.01 (m, 2H), 3.91 (m, 2H), 3.75 (s, 3H),2.07 (s, b, 1H). MS (ES⁺) m/e 169. mp 68.5–69.0° C.

c) 2-(4-Methoxy-phenoxy)-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-(4-methoxy-phenoxy)-ethanol-1 (504 mg, 2 mmol) was converted into2-(4-methoxy-phenoxy)-ethyl tosylate (245 mg, 25%) as a white solid.

¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.14 Hz), 7.31 (d, 2H, J=8.14 Hz),6.68–6.79 (m, 4H), 4.29–4.34 (m, 2H), 4.05–4.11 (m, 2H), 3.73 (s, 3H),2.42 (s, 3H). MS (ES⁺) m/e 323. mp 87.0–88.0° C.

d) Methyl 2-(4-Methoxy-phenoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g),2-(4-methoxy-phenoxy)-ethyl tosylate (245 mg, 0.76 mmol) was convertedinto methyl 2-(4-methoxy-phenoxy)-ethylsulfanyl-acetate (191 mg, 98%) asa colorless oil.

¹H NMR (CDCl₃) δ 6.81 (m, 4H), 4.11 (t, 2H, J=6.37 Hz), 3.74 (s, 3H),3.71 (s, 3H), 3.34 (s, 2H), 2.98 (t, 2H, J=6.37 Hz). MS (ES⁺) m/e 257.

e) 2-(4-Methoxy-phenoxy)-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(4-methoxy-phenoxy)-ethylsulfanyl-acetate (191 mg, 0.76 mmol) wasconverted into 2-(4-methoxy-phenoxy)-ethylsulfanyl acetic acid (144 mg,79%) as a white solid.

¹H NMR (CDCl₃) δ 6.81 (s, 4H), 4.14 (t, 2H, J=6.01 Hz), 3.74 (s, 3H),3.39 (s, 2H), 3.01 (t, 2H, J=6.01 Hz). MS (ES⁺) m/e 241. mp 68.5–69.0°C.

f)[3-(4-{5-[2-(4-Methoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-(4-methoxy-phenoxy)-ethylsulfanyl acetic acid (121 mg, 0.5 mmol) wasconverted into[3-(4-{5-[2-(4-methoxy-phenoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine(85 mg, 39%) as a white solid.

¹H NMR (CDCl₃) δ 7.92 (d, 2H, J=8.85 Hz), 6.97 (d, 2H, J=8.85 Hz),6.75–6.84 (m, 4H), 4.12 (t, 2H, J=6.19 Hz), 4.07 (t, 2H, J=6.37 Hz),4.00 (s, 2H), 3.73 (s, 3H), 3.00 (t, 2H, J=6.19 Hz), 2.45 (t, 2H, J=7.25Hz), 2.25 (s, 6H), 1.97 (m, 2H, J=6.37, 7.25 Hz). MS (ES⁺) m/e 444. mp77.5–78.0° C. Anal. Calcd for C₂₃H₂₉N₃O₄S: C, 62.28; H, 6.59; N, 9.47;S, 7.23. Found C, 62.01; H, 6.60; N, 9.35; S, 7.26.

Example 278 Preparation of[3-(4-{5-[2-(1-naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) 2-(1-Naphthoxy)-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-(1-naphthoxy)-ethanol-1 (565 mg, 2 mmol) was converted into2-(1-naphthoxy)-ethyl tosylate (757 mg, 74%) as a white solid.

¹H NMR (CDCl₃) δ 7.81 (d, 2H, J=8.49 Hz), 7.73 (d, 1H, J=8.14 Hz), 7.69(d, 1H, J=9.91 Hz), 7.67 (t, 1H, J=8.32 Hz), 7.41 (t, 1H, J=8.14 Hz),7.33 (d, 1H, J=8.14), 7.30 (d, 2H, J=7.78 Hz), 6.97–7.02 (m, 2H),4.40–4.44 (m, 2H), 4.22–4.28 (m, 2H), 2.40 (s, 3H). MS (ES⁺) m/e 343. mp93.0–94.0° C.

b) Methyl 2-(1-naphthoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g),2-(1-naphthoxy)-ethyl tosylate (685 mg, 2 mmol) was converted intomethyl 2-(1-naphthoxy)-ethylsulfanyl-acetate (552 mg, 100%) as acolorless oil.

¹H NMR (CDCl₃) δ 8.21–8.27 (m, 1H), 7.74–7.81 (m, 1H), 7.39–7.51 (m,3H), 7.34 (t, 1H, J=7.79 Hz), 6.79 (t, 1H, J=7.08 Hz), 4.36 (t, 2H,J=6.37 Hz), 3.71 (s, 3H), 3.39 (s, 2H), 3.17 (t, 2H, J=6.37 Hz). MS(ES⁺) m/e 277.

c) 2-(1-Naphthoxy)-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(1-naphthoxy)-ethylsulfanyl-acetate (552 mg, 2 mmol) was convertedinto 2-(1-naphthoxy)-ethylsulfanyl acetic acid (500 mg, 95%) as a whitesolid.

¹H NMR (CDCl₃) δ 8.20–8.28 (m, 1H), 7.74–7.82 (m, 1H), 7.44–7.50 (m,2H), 7.42 (d, 1H, J=8.49 Hz), 7.84 (dd, 1H, J=7.78, 8.49 Hz), 6.79 (d,1H, J=7.78 Hz), 4.37 (t, 2H, J=6.01 Hz), 3.42 (s, 2H), 3.20 (t, 2H,J=6.01 Hz). MS (ES) m/e 261. mp 64.5–65.5° C.

d)[3-(4-{5-[2-(1-Naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-(1-naphthoxy)-ethylsulfanyl acetic acid (262 mg, 1 mmol) was convertedinto[3-(4-{5-[2-(1-naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine(344 mg, 74%) as a white solid.

¹H NMR (CDCl₃) δ 8.23–8.28 (m, 1H), 7.88–7.95 (m, 2H), 7.73–7.78 (m,1H), 7.38–7.49 (m, 3H), 7.33 (t, 1H, J=8.02 Hz), 6.92–6.98 (m, 2H), 6.78(d, 1H, J=7.43 Hz), 4.37 (t, 2H, J=6.01 Hz), 4.06 (t, 2H, J=6.37 Hz),4.05 (s, 2H), 3.18 (t, 2H, J=6.01 Hz), 2.46 (t, 2H, J=7.80 Hz), 2.25 (s,6H), 1.97 (m, 2H, J=6.37, 7.80 Hz). MS (ES⁺) m/e 464. mp 101.0–102.0° C.Anal. Calcd for C₂₆H₂₉N₃O₃S: C, 67.36; H, 6.31; N, 9.06; S, 6.92. FoundC, 67.07; H, 6.23; N, 8.98; S, 6.61.

Example 279 Preparation of[3-(4-{5-[2-(2-naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

a) 2-(2-Naphthoxy)-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-(2-naphthoxy)-ethanol-1 (565 mg, 2 mmol) was converted into2-(2-naphthoxy)-ethyl tosylate (646 mg, 63%) as a white solid.

¹H NMR (CDCl₃) δ 8.01 (d, 1H, J=8.85 Hz), 7.80 (d, 2H, J=8.49 Hz), 7.76(d, 1H, J=7.78 Hz), 7.46 (t, 1H, J=8.14 Hz), 7.40 (t, 2H, J=8.49 Hz),7.29 (t, 1H, J=7.78 Hz), 7.24–7.28 (m, 2H), 6.67 (d, 1H, J=7.43 Hz),4.50 (t, 2H, J=4.60 Hz), 4.31 (t, 2H, J=4.60 Hz), 2.39 (s, 3H). MS (ES⁺)m/e 343. mp 79.0–80.0° C.

b) Methyl 2-(2-naphthoxy)-ethylsulfanyl acetate

In a similar manner as exemplified in Example 274 part g),2-(2-naphthoxy)-ethyl tosylate (514 mg, 1.5 mmol) was converted intomethyl 2-(1-naphthoxy)-ethylsulfanyl-acetate (414 mg, 100%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.68–7.76 (m, 3H), 7.42 (q, 1H, J=6.72, 8.14 Hz), 7.32(q, 1H, J=6.72, 7.08 Hz), 7.12 (d, 1H, J=8.14 Hz), 7.11 (s, 1H), 4.29(t, 2H, J=6.37 Hz), 3.72 (s, 3H), 3.38 (s, 2H), 3.08 (t, 2H, J=6.37 Hz).MS (ES⁺) m/e 277.

c) 2-(2-Naphthoxy)-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(2-naphthoxy)-ethylsulfanyl-acetate (414 mg, 1.5 mmol) was convertedinto 2-(2-naphthoxy)-ethylsulfanyl acetic acid (345 mg, 88%) as a whitesolid.

¹H NMR (CDCl₃) δ 7.66–7.77 (m, 3H), 7.42 (t, 1H, J=8.14 Hz), 7.32 (t,1H, J=8.14 Hz), 7.08–7.15 (m, 2H), 4.30 (t, 2H, J=6.01 Hz), 3.38 (s,2H), 3.08 (t, 2H, J=6.01 Hz). MS (ES⁻) m/e 261. mp 99.5–100.5° C.

d)[3-(4-{5-[2-(2-Naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-(2-naphthoxy)-ethylsulfanyl acetic acid (262 mg, 1 mmol) was convertedinto[3-(4-{5-[2-(2-naphthoxy)-ethylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-phenoxy)-propyl]-dimethyl-amine(291 mg, 63%) as a white solid.

¹H NMR (CDCl₃) δ 7.89 (d, 2H, J=8.85 Hz), 7.73 (d, 1H, J=8.14 Hz), 7.69(t, 2H, J=8.14 Hz), 7.41 (q, 1H, J=7.08, 7.78 Hz), 7.31 (q, 1H, J=6.72,7.08 Hz), 7.09–7.14 (m, 2H), 6.91 (d, 2H, J=8.85 Hz), 4.30 (t, 2H,J=6.01 Hz), 4.05 (s, 2H), 4.04 (t, 2H, J=6.37 Hz), 3.10 (t, 2H, J=6.01Hz), 2.44 (t, 2H, J=7.16 Hz), 2.24 (s, 6H), 1.96 (m, 2H, J=6.37, 7.16Hz). MS (ES⁺) m/e 464. mp 97.0–98.0° C. Anal. Calcd for C₂₆H₂₉N₃O₃S: C,67.36; H, 6.31; N, 9.06; S, 6.92. Found C, 66.89; H, 6.41; N, 8.95; S,6.89.

Example 280 Preparation of(3-{4-[5-(2-tert-butoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

a) 2-tert-Butoxy-ethyl tosylate

In a similar manner as exemplified in Example 274 part f),2-tert-butoxy-ethanol-1 (2.36 g, 20 mmol) was converted into2-tert-butoxy-ethyl tosylate (5.21 g, 96%) as a colorless oil.

¹H NMR (CDCl₃) δ 7.78 (d, 2H, J=8.14 Hz), 7.31 (d, 2H, J=8.14 Hz), 4.09(t, 2H, J=5.13 Hz), 3.52 (t, 2H, J=5.13 Hz), 2.42 (s, 3H), 1.10 (s, 9H).MS (ES⁺) m/e 273.

b) Methyl 2-(2-tert-butoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g),2-tert-butoxy-ethyl tosylate (5.21 g, 19 mmol) was converted into methyl2-tert-butoxy-ethylsulfanyl-acetate (3.94 g, 100%) as a colorless oil.

¹H NMR (CDCl₃) δ 3.71 (s, 3H), 3.54 (t, 2H, J=6.55 Hz), 3.30 (s, 2H),2.75 (t, 2H, J=6.55 Hz), 1.17 (s, 9H). MS (ES⁺) m/e 207.

c) 2-tert-Butoxy-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(2-tert-butoxy)-ethylsulfanyl-acetate (3.94 g, 19 mmol) was convertedinto 2-tert-butoxy-ethylsulfanyl acetic acid (3.30 g, 90%) as acolorless oil.

¹H NMR (CDCl₃) δ 3.63 (t, 2H, J=6.01 Hz), 3.35 (s, 2H), 2.80 (t, 2H,J=6.01 Hz), 1.20 (s, 9H). MS (ES⁻) m/e 191.

d)(3-{4-[5-(2-tert-Butoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-tert-butoxy-ethylsulfanyl acetic acid (777 mg, 4 mmol) was convertedinto(3-{4-[5-(2-tert-Butoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(590 mg, 37%) as a brown oil.

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.85 Hz), 6.97 (d, 2H, J=8.85 Hz), 4.06(t, 2H, J=6.37 Hz), 3.97 (s, 2H), 3.55 (t, 2H, J=6.29 Hz), 2.78 (t, 2H,J=6.29 Hz), 2.44 (t, 2H, J=7.26 Hz), 2.24 (s, 6H), 1.96 (m, 2H, J=6.37,7.26 Hz), 1.16 (s, 9H). MS (ES⁺) m/e 394.

e)(3-{4-[5-(2-tert-Butoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-aminemaleate

To a hot solution of maleic acid (193 mg, 1.7 mmol) in ethyl acetate (1mL) was added a solution of(3-{4-[5-(2-tert-Butoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(590 mg, 1.5 mmol) in ethyl acetate with stirring. After 10 minutes,solvent was removed on a rotary evaporator. The oily residue wasdissolved in dichloromethane (1 mL) followed by addition of diethylether (20 mL). The mixture was rapidly stirred at 23° C. till solidformed. The solid was collected by filtration, washed with diethyl ether(3×5 mL), and dried in vacuum to provide a light brown solid (300 mg,39%).

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.85 Hz), 6.94 (d, 2H, J=8.85 Hz), 6.22(s, 2H), 4.13 (t, 2H, J=5.48 Hz), 3.97 (s, 2H), 3.56 (t, 2H, J=6.19 Hz),3.27 (t, 2H, J=7.96 Hz), 2.87 (s, 6H), 2.77 (t, 2H, J=6.19 Hz),2.22–2.34 (m, 2H), 1.16 (s, 9H). MS (ES⁺) m/e 394. mp 84.5–85.5° C.Anal. Calcd for C₂₄H₃₅N₃O₇S: C, 56.56; H, 6.92; N, 8.25; S, 6.29. FoundC, 56.33; H, 6.85; N, 8.36; S, 6.03.

Example 281 Preparation of(3-{4-[5-(2-methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

a) Methyl 2-(2-methoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g), 2-bromoethylmethyl ether (1.39 g, 10 mmol) was converted into methyl2-(2-methoxy)-ethylsulfanyl-acetate (1.06 g, 64%) as a colorless oil.

¹H NMR (CDCl₃) δ 3.71 (s, 3H), 3.57 (t, 2H, J=6.37 Hz), 3.33 (s, 3H),3.27 (s, 2H), 2.80 (t, 2H, J=6.37 Hz). MS (ES⁺) m/e 165.

b) 2-Methoxy-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(2-methoxy)-ethylsulfanyl-acetate (1.06 g, 19 mmol) was converted into2-methoxy-ethylsulfanyl acetic acid (0.84 g, 87%) as a colorless oil.

¹H NMR (CDCl₃) δ 3.62 (t, 2H, J=6.01 Hz), 3.36 (s, 3H), 3.32 (s, 2H),2.84 (t, 2H, J=6.01 Hz). MS (ES⁻) m/e 149.

c)(3-{4-[S-(2-Methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-methoxy-ethylsulfanyl acetic acid (549 mg, 3.7 mmol) was convertedinto(3-{4-[5-(2-methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(900 mg, 69%) as a white solid.

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.85 Hz), 6.95 (d, 2H, J=8.85 Hz), 4.15(t, 2H, J=5.66 Hz), 3.94 (s, 2H), 3.58 (t, 2H, J=6.01 Hz), 3.32 (s, 3H),3.19–3.26 (m, 2H), 2.83 (s, 6H), 2.81 (m, 2H, J=6.01 Hz), 2.37–2.46 (m,2H). MS (ES⁺) m/e 352.

d)(3-{4-[5-(2-Methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-aminemaleate

In a similar manner as exemplified in Example 280 part e),(3-{4-[5-(2-methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(300 mg, 0.85 mmol) was converted(3-{4-[5-(2-methoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-aminemaleate (278 mg, 70%) as a white solid.

¹H NMR (CDCl₃) δ 7.97 (d, 2H, J=8.85 Hz), 6.95 (d, 2H, J=8.85 Hz), 6.23(s, 2H), 4.13 (t, 2H, J=5.66 Hz), 3.95 (s, 2H), 3.59 (t, 2H, J=6.01 Hz),3.33 (s, 3H), 3.26 (t, 2H, J=7.96 Hz), 2.86 (s, 6H), 2.82 (t, 2H, J=6.01Hz), 2.24–2.84 (m, 2H). MS (ES³⁰ ) m/e 352. mp 97.5–99.0° C. Anal. Calcdfor C₂₁H₂₉N₃O₇S: C, 53.95; H, 6.25; N, 8.99; S, 6.86. Found C, 53.83; H,6.26; N, 8.92; S, 6.99.

Example 282 Preparation of(3-{4-[5-(2-phenylmethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

a) Methyl 2-(2-phenylmethoxy)-ethylsulfanyl-acetate

In a similar manner as exemplified in Example 274 part g), benzyl2-bromoethyl ether (2.15 g, 10 mmol) was converted into methyl2-(2-phenylmethoxy)-ethylsulfanyl-acetate (2.19 g, 91%) as a colorlessoil.

¹H NMR (CDCl₃) δ 7.21–7.39 (m, 5H), 4.52 (s, 2H), 3.69 (s, 3H), 3.66 (t,2H, J=6.37 Hz), 3.28 (s, 2H), 2.85 (t, 2H, J=6.37 Hz). MS (ES⁺) m/e 241.

b) 2-Phenylmethoxy-ethylsulfanyl acetic acid

In a similar manner as exemplified in Example 274 part h), methyl2-(2-phenylmethoxy)-ethylsulfanyl-acetate (2.16 g, 9 mmol) was convertedinto 2-phenylmethoxy-ethylsulfanyl acetic acid (1.89 g, 92%) as acolorless oil.

¹H NMR (CDCl₃) δ 7.23–7.36 (m, 5H), 4.53 (s, 2H), 3.69 (t, 2H, J=6.19Hz), 3.32 (s, 2H), 2.87 (t, 2H, J=6.19 Hz). MS (ES⁻) m/e 225.

c)(3-{4-[5-(2-Phenylmethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

In a similar manner as exemplified in Example 274 part i),2-phenylmethoxy-ethylsulfanyl acetic acid (675 mg, 3 mmol) was convertedinto(3-{4-[5-(2-phenymethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(994 mg, 78%) as a white solid.

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.85 Hz), 7.21–7.34 (m, 5H), 6.97 (d,2H, J=8.85 Hz), 4.52 (s, 2H), 4.06 (t, 2H, J=6.37 Hz), 3.94 (s, 2H),3.67 (t, 2H, J=6.37 Hz), 2.86 (t, 2H, J=6.37 Hz), 2.44 (t, 2H, J=7.26Hz), 2.24 (s, 6H), 1.96 (m, 2H, J=6.37, 7.26 Hz). MS (ES⁺) m/e 428.

d)(3-{4-[5-(2-Phenylmethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-aminemaleate

In a similar manner as exemplified in Example 280 part e),(3-{4-[5-(2-phenylmethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine(497 mg, 1.16 mmol) was converted(3-{4-[5-(2-phenylmethoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-aminemaleate (537 mg, 85%) as a white solid.

¹H NMR (CDCl₃) δ 7.95 (d, 2H, J=8.85 Hz), 7.20–7.34 (m, 5H), 6.94 (d,2H, J=8.85 Hz), 6.25 (s, 2H), 4.52 (s, 2H), 4.13 (t, 2H, J=5.48 Hz),3.95 (s, 2H), 3.68 (t, 2H, J=6.37 Hz), 3.27 (t, 2H, J=7.96 Hz), 2.87 (s,6H), 2.86 (t, 2H, J=6.37 Hz), 2.30 (m, 2H, J=5.48, 7.96 Hz). MS (ES⁺)m/e 428. mp 71.5–72.0° C. Anal. Calcd for C₂₇H₃₃N₃O₇S: C, 59.65; H,6.12; N, 7.73; S, 5.90. Found C, 59.52; H, 6.07; N, 7.73; S, 5.99.

Example 283 Preparation of(3-{2,6-dichloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;fumaric acid salt

a) Methyl 3,5-dichloro-4-(3-dimethylamino-propoxy)-benzoate

17.05 gm (77.1 mmol) of methyl 3,5-dichloro-4-hydroxybenzoate, 22.26 gm(84.9 mmol) of triphenylphosphine, and 10.0 mL (84.9 mmol) of3-dimethylaminopropan-1-ol were dissolved in 100 mL of dry THF and withstirring under dry nitrogen cooled to 0° C. 16.7 ml (84.9 mmol) ofdiisopropylazodicarboxylate was then slowly added over 5 minutes.Stirring was continued at 0° C. for 2 hours and then at room temperaturefor a further 2 hours. The solvents were then removed under reducedpressure to yield an oil. This was diluted with about 100 mL ofethylacetate which was then extracted 3 times with 3N HCl. The aqueousextracts were combined, cooled to 0° C. and solid sodium hydroxide wasadded until the aqueous phase was at least pH 10. The basified aqueousfraction was then extracted twice with 50 ml portions of methylenechloride which were then combined, dried over magnesium sulfate,filtered, and evaporated to give 16.3 gm (70%) of methyl3,5-dichloro-4-(3-dimethylamino-propoxy)-benzoate as a thick syrup.

¹H NMR (CHCl₃-d1) δ 7.91 (s, 1H), 4.09 (t, 2H, J=6.37 Hz), 3.86 (s, 3H),2.49 (t, 2H, J=7.78 Hz), 2.22 (s, 6H), 1.95–2.02 (m, 2H).

b) 3,5-Dichloro-4-(3-dimethylamino-propoxy)-benzoic acid hydrazide

5.01 gm (16.43 mmol) of methyl3,5-dichloro-4-(3-dimethylamino-propoxy)-benzoate was dissolved in 15 mLof ethanol and 15 ml of hydrazine hydrate were added. The mixture washeated at 90° C. for 5.5 h and then cooled to room temperature. Themixture was diluted with about 100 mL of methylene chloride, which wasthen washed with about 30 mL of water. The aqueous layer was washed oncewith about 30 ml of ethylacetate and then the organic fractions werecombined, dried over magnesium sulfate, filtered, and evaporated toyield 3.56 gm (71%) of 3,5-dichloro-4-(3-dimethylamino-propoxy)-benzoicacid hydrazide as a waxy solid.

¹H NMR (CHCl₃-d1) δ 7.69 (s, 2H), 4.08 (t, 2H, J=6.72 Hz), 2.50 (t, 2H,J=7.78 Hz), 2.23 (s, 6H), 1.95–2.02 (m, 2H).

c)(3-{2,6-Dichloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;fumaric acid salt

3.05 gm (10.0 mmol) of 3,5-dichloro-4-(3-dimethylamino-propoxy)-benzoicacid hydrazide, 2.12 gm (10.0 mmol) of (2-phenoxy-ethylsulfanyl)-aceticacid, 7.87 gm (30.0 mmol) of triphenylphosphine, 8.3 ml (60.0 mmol) oftriethylamine, were suspended in 25 mL of dry acetonitrile and stirredat room temperature. 4.8 mL (50.0 mmol) of carbon tetrachloride was thenslowly added. The resultant mixture was stirred at room temperature forabout 5 hours and then the solvent was removed under reduced pressure.The resultant oil was diluted with about 50 mL of ethylacetate which wasthen extracted with two portions of about 15 mL 3N HCl. The combinedacidic extracts were basified with solid sodium hydroxide and thenextracted with two approximately 30 mL portions of methylene chloride.The methylene chloride extracts were dried over magnesium sulfate,filtered, and then evaporated to yield 3.94 gm of a dark red oil. Theoil was chromatographed on about 100 gm of silica gel using sequentially500 mL of ethylacetate, a 1,000 mL gradient of from 0 to 40% methanol inethylacetate and then 1,000 mL of 40% methanol in methylene chloride togive 1.45 gm of the desired free base. This was dissolved in a mixtureof ethylacetate and methylene chloride and 344 mg of fumaric acid wasadded. The solvents were evaporated and the residue was triturated indiethyl ether to give 1.48 gm of(3-{2,6-dichloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;fumaric acid salt as a solid. mp=95–99° C.

¹H NMR (CH₃OH-d4) δ 7.97 (s, 2H), 7.18 (t, 2H, J=8.14 Hz), 6.81–6.87 (m,3H), 6.66 (s, 2H), 4.21 (t, 2H, J=5.66 Hz), 4.13–4.17 (m, 4H), 3.40–3.46(m, 2H), 3.03 (t, 2H, J=6.01 Hz), 2.91 (s, 6H), 2.23–2.32 (m, 2H).

Anal. Calcd for C₂₆H₂₉Cl₂N₃O₇S: C, 52.18; H, 4.88; N, 7.02; Cl, 11.85.Found C, 52.20; H, 4.74; N, 7.88; Cl, 11.86.

Example 284 Preparation of(3-{2-methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

a) Methyl 4-(3-dimethylamino-propoxy)-3-methoxy benzoate

In a similar manner as exemplified in Example 283 part a), 10.0 gm ofmethyl 4-hydroxy-3-methoxybenzoate was converted into 16.08 gm of methyl4-(3-dimethylamino-propoxy)-3-methoxy benzoate as a yellow oil.

¹H NMR (CHCl₃-d1) δ 7.60 (dd, 1H, J=8.49, 2.12 Hz), 7.50 (d, 1H, J=2.12Hz), 6.86 (d, 1H, J=8.49 Hz), 4.09 (t, 2H, J=6.72 Hz), 3.87 (s, 3H),3.84 (s, 3H), 2.41 (t, 2H, J=7.08 Hz), 2.20 (s, 6H), 1.94–2.04 (m, 2H).

b) 4-(3-Dimethylamino-propoxy)-3-methoxy benzoic acid hydrazide

In a similar manner as exemplified in Example 283 part b), 16 gm ofmethyl 4-(3-dimethylamino-propoxy)-3-methoxy benzoate was converted into4-(3-dimethylamino-propoxy)-3-methoxy benzoic acid hydrazide a portionof which was purified by chromatography on silica gel using a 6% 2Nammonia in methanol mixture in methylene chloride to yield 1.35 gm of awhite solid.

¹H NMR (CHCl₃-d1) δ 8.06 (bs, 1H), 7.83 (d, 1H, J=2.12 Hz), 7.22 (dd,1H, J=8.40 Hz), 6.80 (d, 1H, J=8.49 Hz), 4.02 (t, 2H, J=6.72 Hz), 3.81(s, 3H), 2.38 (t, 2H, J=7.43 Hz, 2.17 (s, 6H), 1.90–1.99 (m, 2H).

c)(3-{2-Methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

In a similar manner as exemplified in Example 283 part c), 1.37 gm of4-(3-dimethylamino-propoxy)-3-methoxy benzoic acid hydrazide wasconverted into 1.62 gm of(3-{2-methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt except: The initial reaction mixture was evaporated todryness, taken up in ethyl acetate, and washed with saturated sodiumbicarbonate. The organic phase was dried over magnesium sulfate,filtered, and evaporated to yield a solid which was chromatographed onabout 100 gm of silica gel using 500 mL of ethylacetate, a 500 mLgradient of a 0 to 5% 2N ammonia in methanol mixture in methylenechloride, and 1,500 mL of a 5% 2N ammonia in methanol mixture inmethylene chloride. The free base was converted into the maleic acidsalt by addition of an equivalent of maleic acid to the free base in hotethyl acetate. The desired salt precipitated from solution as a whitesolid which was collected by filtration. mp=114–116° C.

¹H NMR (CH₃OH-d4) δ 7.54–7.58 (m, 2H), 7.19 (t, 2H, J=8.14 Hz), 7.09 (d,1H, J=8.85 Hz), 6.84–6.90 (m, 2H), 6.20 (s, 2H), 4.22 (t, 2H, J=5.66Hz), 4.17 (t, 2H, J=6.01 Hz), 4.13 (s, 2H), 3.90 (s, 3H), 3.38 (t, 2H,J=7.08 Hz), 3.03 (t, 2H, J=6.01 Hz), 2.96 (s, 6H), 2.23–2.31 (m, 2H).

Anal. Calcd for C₂₇H₃₃N₃O₈S: C, 57.95; H, 5.94; N, 7.51. Found C, 58.02;H, 5.89; N, 7.49.

Example 285 Preparation of(3-{2,6-dimethoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

a) Methyl 3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoate

In a similar manner as exemplified for Example 283, part a), 5.0 gm(23.56 mmol) of methyl 3,5-dimethoxy-4-hydroxybenzoate was convertedinto 6.96 gm (100%) of methyl3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoate as a yellow oil.

¹H NMR (CHCl₃-d1) δ 7.25 (s, 2H), 4.05 (t, 2H, J=6.72 Hz), 3.86 (s, 3H),3.85 (s, 6H), 2.44 (t, 2H, J=7.08 Hz), 2.20 (s, 6H), 1.84–1.93 (m, 2H).

b) 3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoic acid hydrazide

In a similar manner as exemplified for Example 283, part b), 2.49 gm ofmethyl 3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoate was convertedinto 1.99 gm (80%) of 3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoicacid hydrazide as a white waxy solid excepting that the reaction wascarried out at room temperature for 24 h. mp=95–96° C.

¹H NMR (CHCl₃-d1) δ 6.93 (s, 2H), 4.02 (t, 2H, J=6.72 Hz), 3.84 (s, 6H),2.44 (t, 2H, J=7.08 Hz, 2.21 (s, 6H), 1.84–1.93 (m, 2H).

c)(3-{2,6-Dimethoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

In a similar manner as exemplified for Example 284 part c), 1.06 gm of3,5-dimethoxy-4-(3-dimethylamino-propoxy)-benzoic acid hydrazide wasconverted into 1.20 gm of(3-{2,6-dimethoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt as a white solid except that 2N sodium hydroxide wassubstituted for the saturated sodium bicarbonate in the ethyl acetatewash. mp=103–104° C.

¹H NMR (CH₃OH-d4) δ 7.30 (s, 2H), 7.19 (t, 2H, J=7.78 Hz), 6.84–6.89 (m,2H), 6.22 (s, 2H), 4.13–4.19 (m, 6H), 3.91 (s, 6H), 3.45 (t, 2H, J=6.72Hz), 3.04 (t, 2H, J=6.01 Hz), 2.96 (s, 6H), 2.12–2.19 (m, 2H).

Anal. Calcd for C₂₈H₃₅N₃O₉S: C, 57.03; H, 5.98; N, 7.13. Found C, 57.01;H, 5.84; N, 7.10.

Example 286 Preparation of(3-{2-chloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

a) Methyl 3-chloro-4-(3-dimethylamino-propoxy)-benzoate

In a similar manner as exemplified for Example 283, part a), 5.01 gm ofmethyl 3-chloro-4hydroxybenzoate was converted into 6.39 gm of methyl3-chloro-4-(3-dimethylamino-propoxy)-benzoate as a yellow oil.

¹H NMR (CHCl₃-d1) δ 8.00 (d, 1H, J=2.12 Hz), 7.86 (dd, 1H, J=8.49, 2.12Hz), 6.91 (d, 1H, J=8.85 Hz), 4.11 (t, 2H, J=6.72 Hz), 3.85 (s, 3H),2.45 (t, 2H, J=7.08 Hz), 2.22 (s, 6H), 1.94–2.03 (m, 2H).

b) 3-Chloro-4-(3-dimethylamino-propoxy)-benzoic acid hydrazide

In a similar manner as exemplified for example 285 part b), 6.35 gm ofmethyl 3-chloro-4-(3-dimethylamino-propoxy)-benzoate was converted into5.81 gm of 3-chloro-4-(3-dimethylamino-propoxy)-benzoic acid hydrazideas a white waxy solid.

¹H NMR (CHCl₃-d1) δ 8.06 (bs, 1H), 7.79 (d, 1H, J=2.12 Hz), 7.61 (dd,1H, J=8.40, 2.48 Hz), 6.88 (d, 1H, J=8.85 Hz), 4.07 (t, 2H, J=6.37 Hz),2.44 (t, 2H, J=7.08 Hz), 2.21 (s, 6H), 1.92–2.01 (m, 2H).

c)(3-{2-Chloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

In a similar manner as exemplified for example 284 part c), 2.49 gm of3-chloro-4-(3-dimethylamino-propoxy)-benzoic acid hydrazide wasconverted into 1.84 gm of(3-{2-chloro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt as a white solid.

¹H NMR (CH₃OH-d4) δ 7.99 (d, 1H, J=2.12 Hz), 7.90 (dd, 1H, J=8.85, 2.12Hz), 7.16–7.26 (m, 3H), 6.83–6.89 (m, 3H), 6.21 (s, 2H), 4.27 (t, 2H,J=5.66 Hz), 4.17 (t, 2H, J=6.01 Hz), 4.13 (s, 2H), 3.38 (t, 2H, J=7.43),3.03 (t, 2H, J=6.01 Hz), 2.95 (s, 6H), 2.26–2.85 (m, 2H).

Anal. Calcd for C₂₆H₃₀ClN₃O₇S: C, 55.36; H, 5.36; N, 7.45; Cl, 6.29.Found C, 55.50; H, 5.24; N, 7.37, Cl, 6.29.

Example 287 Preparation of(3-{2-fluoro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

a) Methyl 4-(3-dimethylamino-propoxy)-3-fluoro benzoate

In a similar manner as exemplified in Example 283 part a), 2.82 gm ofmethyl 3-fluoro-4-hydroxybenzoate was converted into 3.95 gm of methyl4-(3-dimethylamino-propoxy)-3-fluoro benzoate as a yellow oil.

¹H NMR (CHCl₃-d1) δ 7.74 (d, 1H, J=9.20 Hz), 7.69 (d, 1H, J=9.55 Hz),4.11 (t, 2H, J=6.37 Hz), 3.84 (s, 3H), 2.42 (t, 2H, 6.72 Hz), 2.21 (s,6H), 1.92–2.01 (m, 2H).

b) 4-(3-Dimethylamino-propoxy)-3-fluoro benzoic acid hydrazide

In a similar manner as exemplified in Example 285 part b), 3.84 gm ofmethyl 4-(3-dimethylamino-propoxy)-3-fluoro benzoate was converted into3.51 gm of 4-(3-dimethylamino-propoxy)-3-fluoro benzoic acid hydrazideas a white solid. mp=109–111° C.

¹H NMR (CHCl₃-d1) δ 7.41–7.51 (m, 2H), 6.97 (t, 1H, J=8.49), 4.10 (t,2H, J=6.72 Hz), 2.43 (t, 2H, J=7.08 Hz), 2.22 (s, 6H), 1.93–2.02 (m,2H).

c)(3-{2-Fluoro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt

In a similar manner as exemplified in example 284 part c), 1.01 gm of4-(3-dimethylamino-propoxy)-3-fluoro benzoic acid hydrazide wasconverted into 448 mg of(3-{2-fluoro-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine;maleic acid salt as a beige solid. mp=70–72° C.

¹H NMR (CH₃OH-d4) δ 7.76 (d, 1H, J=8.85 Hz), 7.72 (d, 1H, J=11.32 Hz),7.26 (t, 1H, J=8.49 Hz), 7.19 (t, 2H, J=8.85 Hz), 6.84–6.90 (m, 3H),6.22 (s, 2H), 4.26 (t, 2H, J=5.66 Hz), 4.18 (t, 2H, J=6.01 Hz), 4.13 (s,2H), 3.35 (t, 2H, J=7.43 Hz), 3.03 (t, 2H, J=6.37 Hz), 2.93 (s, 6H),2.23–2.32 (m, 2H).

Anal. Calcd for C₂₆H₃₀FN₃O₇S: C, 57.03; H, 5.52; N, 7.67. Found C,56.68; H, 5.32; N, 7.71.

Example 288 Preparation ofdimethyl-(3-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yloxy}-propyl)-amine

a) 6-(3-Dimethylamino-propoxy)-nicotinic acid benzyl ester

In a similar manner as exemplified for Example 283, part a), 5.0 gm ofbenzyl 6-hydroxynicotinate was converted into a 50:50 mixture of6-(3-dimethylamino-propoxy)-nicotinic acid benzyl ester and it'sN-alkylated isomer as a light yellow oil.

b) 6-(3-Dimethylamino-propoxy)-nicotinic acid hydrazide

In a similar manner as exemplified in example 285 part b), 7.0 gm of a50:50 mixture of 6-(3-dimethylamino-propoxy)-nicotinic acid benzyl esterand it's N-alkylated isomer were converted into a mixture of N- andO-alkylated hydrazides which was separated by chromatography on silicagel using a 0 to 10% gradient of a 2N ammonia in methanol mixture inmethylene chloride. 1.96 gm of 6-(3-dimethylamino-propoxy)-nicotinicacid hydrazide was obtained as a white solid. mp=81–83° C.

¹H NMR (CHCl₃-d1) δ 8.50 (s, 1H), 7.93 (d, 1H, J=10.61 Hz), 7.86 (bs,1H), 6.73 (d, 1H, J=8.85 Hz), 4.35 (t, 2H, J=6.72 Hz), 2.45 (t, 2H,J=7.08 Hz), 2.25 (s, 6H), 1.87–2.00 (m, 2H).

c)Dimethyl-(3-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yloxy}-propyl)-amine

In a similar manner as exemplified in example 284, part c), 1.00 gm of6-(3-dimethylamino-propoxy)-nicotinic acid hydrazide was converted into774 mg of the free basedimethyl-(3-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yloxy}-propyl)-amineas a white solid. mp=69–70° C.

¹H NMR (CHCl₃-d1) δ 8.67 (d, 1H, J=1.77 Hz), 8.13 (dd, 1H, J=8.85, 2.48Hz), 7.24 (t, 2H, J=8.85), 6.92 (t, 1H, J=7.43 Hz), 6.92 (t, 1H, J=7.43Hz), 6.86 (d, 2H, J=7.78 Hz), 6.80 (d, 1H, J=8.85 Hz), 4.40 (t, 2H, 6.72Hz), 4.18 (t, 2H, J=6.37 Hz), 4.03 (s, 2H), 3.03 (t, 2H, J=6.01 Hz),2.42 (t, 2H, J=7.08 Hz), 2.24 (s, 6H), 1.91–1.99 (m, 2H). Anal. Calcdfor C₂₁H₂₆N₄O₃S: C, 60.85; H, 6.32; N, 13.52. Found C, 61.07; H, 6.28;N, 13.46.

Example 289 Preparation ofdimethyl-(3-{6-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yloxy}-propyl)-amine

a) 5-(3-Dimethylamino-propoxy)-pyridine-2-carboxylic acid methyl ester

504.4 mg (3.29 mmol) of 5-hydroxy-pyridine-2-carboxylic acid methylester, 864 mg (3.29 mmol) of triphenylphosphine, and 390 uL of3-dimethylaminopropan-1-ol were combined and stirred under dry nitrogenin 10 mL of dry THF at 0° C. 650 uL (3.29 mmol) ofdiisopropylazodicarboxylate was then slowly added over 3 minutes withcontinued stirring at 0° C. for 1 hour and then at room temperature fora further 3 hours. The solvents were removed under reduced pressure andthe resultant oil was chromatographed on about 100 gm of silica gelusing 240 ml of ethylacetate, then 500 ml of a gradient of from 0 to 5%of a 2N ammonia in methanol mixture in methylene chloride, and then 1 Lof a 5% 2N ammonia in methanol mixture in methylene chloride to give602.3 mg (77%) of 5-(3-dimethylamino-propoxy)-pyridine-2-carboxylic acidmethyl ester as a yellow waxy solid. mp 44–45° C.

¹H NMR (CHCl₃-d1) δ 8.36 (d, 1H, J=2.48 Hz), 8.07 (d, 1H, J=8.85 Hz),7.23 (dd, 1H, J=8.84, 2.83 Hz), 4.11 (t, 2H, J=6.37 Hz), 3.95 (s, 2H),2.43 (t, 2H, J=7.08 Hz), 2.23 (s, 6H), 1.93–2.01 (m, 2H).

b) 5-(3-Dimethylamino-propoxy)-pyridine-2-carboxylic acid hydrazide

In a similar manner as exemplified in example 285 part b), 1.4 gm of5-(3-dimethylamino-propoxy)-pyridine-2-carboxylic acid methyl ester wasconverted into 1.38 gm of5-(3-dimethylamino-propoxy)-pyridine-2-carboxylic acid hydrazide as alight brown waxy solid. mp=82–83° C.

¹H NMR (CHCl₃-d1) δ 8.67 (bs, 1H), 8.16 (d, 1H, J=2.48 Hz), 8.05 (d, 1H,J=8.85 Hz), 7.25 (dd, 1H, J=8.49, 2.83 Hz), 4.08 (t, 2H, J=6.37 Hz),2.42 (t, 2H, J=7.08 Hz), 2.22 (s, 6H), 1.91–2.00 (m, 2H).

c)Dimethyl-(3-{6-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yloxy}-propyl)-amine

In a similar manner as exemplified for Example 283, part c), 1.00 gm of5-(3-dimethylamino-propoxy)-pyridine-2-carboxylic acid hydrazide wasconverted into 712 mg of the free basedimethyl-(3-{6-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yloxy}-propyl)-amineas a beige solid. mp=47–49° C.

¹H NMR (CHCl₃-d1) δ 8.40 (d, 1H, J=2.83 Hz), 8.12 (d, 1H, J=8.84 Hz),7.80 (dd, 1H, J=8.85, 2.83 Hz), 7.18 (t, 2H, J=8.85 Hz), 6.92 (t, 1H,J=7.43 Hz), 6.87 (d, 2H, J=7.78 Hz), 4.18 (t, 2H, J=6.01 Hz), 4.13 (t,2H, J=6.37 Hz), 4.04 (s, 2H), 3.04 (t, 2H, J=6.37 Hz), 2.45 (t, 2H,J=7.08 Hz), 2.24 (s, 6H), 1.94–2.03 (m, 2H).

Anal. Calcd for C₂₁H₂₆N₄O₃S: C, 60.85; H, 6.32; N, 13.52. Found C,60.82; H, 6.24; N, 13.51.

Example 290 Preparation of1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-piperidine;maleic acid salt

a) 4-(1-Methyl-piperidin-3-ylmethoxy)-benzoic acid methyl ester

In a similar manner as exemplified for Example 283 part a), exceptingthat 3-hydroxymethyl-1-methyl-piperidine was substituted for the3-dimethylaminopropan-1-ol and that the resultant material was purifiedby chromatography on about 100 gm of silica gel using 500 mL ofethylacetate, then 500 mL of a gradient of from 0 to 5% of a 2N ammoniain methanol mixture in methylene chloride, and then 1.8 L of a 5% 2Nammonia in methanol mixture in methylene chloride, 1.5 gm of methyl4-hydroxybenzoate was converted into 1.792 gm of4-(1-methyl-piperidin-3-ylmethoxy)-benzoic acid methyl ester as a whitewaxy solid. mp=55–56° C.

¹H NMR (CHCl₃-d1) δ 7.93 (d, 2H, J=8.85 Hz), 6.86 (d, 2H, J=8.85 Hz),3.77–3.90 (m, 5H), 2.90 (d, 1H, J=9.91 Hz), 2.71 (d, 1H, J=10.97 Hz),2.24 (s, 3H), 2.05–2.17 (m, 1H), 1.92 (bt, 1H), 1.53–1.84 (m, 4H), 1.07(dq, 1H, J=12.03, 3.54 Hz).

b) 4-(1-Methyl-piperidin-3-ylmethoxy)-benzoic acid hydrazide

In a similar manner as exemplified for Example 285, part b), 1.7 gm of4-(1-methyl-piperidin-3-ylmethoxy)-benzoic acid methyl ester wasconverted into 1.7 gm of 4-(1-methyl-piperidin-3-ylmethoxy)-benzoic acidhydrazide as a white solid. mp=170–172° C.

¹H NMR (CHCl₃-d1) δ 7.67 (d, 2H, J=8.84 Hz), 6.89 (d, 2H, J=8.84 Hz),4.04 (bs, 2H), 3.76–3.89 (m, 2H), 2.91 (bd, 1H, J=10.61 Hz), 2.73 (bd,1H, J=10.97 Hz), 2.25 (s, 3H), 2.05–2.18 (m, 1H), 1.94 (bt, 1H, J=10.97Hz), 1.54–1.86 (m, 4H), 1.08 (dq, 1H, J=11.32 Hz).

1-Methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-piperidine;maleic acid salt

In a similar manner as exemplified for Example 285, part c), 800 mg of4-(1-methyl-piperidin-3-ylmethoxy)-benzoic acid hydrazide was convertedinto 620 mg of1-methyl-3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxymethyl}-piperidine;maleic acid salt as a white solid. mp=115–116° C.

¹H NMR (CHCl₃-d1) δ 7.95 (d, 2H, J=8.84 Hz), 7.25 (t, 2H, J=8.85 Hz),6.90–6.98 (m, 3H), 6.87 (d, 2H, J=8.85 Hz), 6.27 (s, 2H), 4.19 (t, 2H,J=6.37 Hz), 3.99–4.05 (m, 3H), 3.86–3.93 (m, 1H), 3.68 (bd, 1H, J=12.38Hz), 3.60 (bd, 1H, J=11.32 Hz), 3.03 (t, 2H, J=6.01 Hz), 2.82 (s, 3H),2.50–2.73 (m, 3H), 1.91–2.15 (m, 3H), 1.48 (dq, 2H, J=13.44, 4.60).

Anal. Calcd for C₂₈H₃₃N₃O₇S: C, 60.53; H, 5.99; N, 7.56. Found C, 60.76;H, 5.90; N, 7.62.

Example 291 Preparation of1-methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-piperidine;maleic acid salt

a) 4-(1-Methyl-piperidin-4-yloxy)-benzoic acid methyl ester

In a similar manner as exemplified in example 290, part a), except that4-hydroxy-1-methyl-piperidine was substituted for3-hydroxymethyl-1-methyl-piperidine, 1.5 gm of methyl 4-hydroxybenzoatewas converted into 743 mg of 4-(1-methyl-piperidin-4-yloxy)-benzoic acidmethyl ester.

¹H NMR (CHCl₃-d1) δ 7.93 (d, 2H, J=9.20 Hz), 6.87 (d, 2H, J=9.20 Hz),4.33–4.42 (m, 1H), 3.84 (s, 3H), 2.59–2.71 (m, 21), 2.21–2.32 (m, 5H),1.93–3.02 (m, 2H), 1.76–1.88 (m, 2H).

b) 4-(1-Methyl-piperidin-4-yloxy)-benzoic acid hydrazide

740 mg of 4-(1-methyl-piperidin-4-yloxy)-benzoic acid methyl ester wasstirred in 3 ml of hydrazine hydrate and 3 ml of ethanol for 24 h. Thesolvents were removed under reduced pressure to yield 740 mg of4-(1-methyl-piperidin-4-yloxy)-benzoic acid hydrazide as a white solid.mp=110–112° C.

¹H NMR (CHCl₃-d1) δ 7.66 (d, 2H, J=8.85 Hz), 6.90 (d, 2H, J=8.49 Hz),4.31–4.41 (m, 1H), 4.04 (bs, 2H), 2.60–2.72 (m, 2H), 2.22–2.33 (m, 5H),1.94–2.05 (m, 2H), 1.77–1.89 (m, 2H).

c)1-Methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-piperidine;maleic acid salt

In a similar manner as exemplified for example 284, part c), 684 mg of4-(1-methyl-piperidin-4-yloxy)-benzoic acid hydrazide was converted into897 mg of1-methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-piperidine;maleic acid salt as a yellow solid. mp=149–150° C.

¹H NMR (CHCl₃-d1) δ 7.98 (d, 2H, J=8.85 Hz), 7.25 (t, 2H, J=7.43 Hz),6.98 (d, 2H, J=8.85 Hz), 6.93 (t, 1H, J=7.08 Hz), 6.87 (d, 2H, J=7.78Hz), 6.28 (s, 2H), 4.78 (bs, 1H), 4.19 (t, 2H, J=6.01 Hz), 4.03 (s, 2H),3.37–3.49 (m, 2H), 3.07–3.21 (m, 2H), 3.03 (t, 2H, J=6.01 Hz), 2.82 (s,3H), 2.35 (bt, 2H, J=13.44 Hz), 2.20 (bd, 2H, J=15.21 Hz).

Anal. Calcd for C₂₇H₃₂N₃O₇S: C, 59.88; H, 5.77; N, 7.76. Found C, 59.85;H, 5.66; N, 7.63.

Example 292 Preparation of(3-{3-methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

a) Methyl 4-(3-dimethylamino-propoxy)-2-methoxy benzoate

In a similar manner as exemplified for example 291, part a), 1.0 gm ofmethyl 2-methoxybenzoate was converted into 1.12 gm of methyl4-(3-dimethylamino-propoxy)-2-methoxy benzoate as a clear oil.

¹H NMR (CHCl₃-d1) δ 7.80 (d, 1H, J=9.20 Hz), 6.43–6.47 (m, 2H), 4.02 (t,2H, J=6.37 Hz), 3.85 (s, 3H), 3.81 (s, 3H), 2.41 (t, 2H, J=7.07 Hz),2.22 (s, 6H), 1.88–1.97 (m, 2H).

b) 4-(3-Dimethylamino-propoxy)-2-methoxy benzoic acid hydrazide

In a similar manner as exemplified in example 291, part b, 1.12 gm ofmethyl 4-(3-dimethylamino-propoxy)-2-methoxy benzoate was converted into1.028 gm of 4-(3-dimethylamino-propoxy)-2-methoxy benzoic acid hydrazideas a white waxy solid. mp=47–52° C.

¹H NMR (CHCl₃-d1) δ 7.98 (d, 1H, J=8.49 Hz), 6.51 (dd, 1H, J=8.85, 2.48Hz), 6.42 (d, 1H, J=2.48 Hz), 3.98 (t, 2H, J=6.01 Hz), 3.87 (s, 3H),2.48 (t, 2H, J=7.43 Hz), 2.25 (s, 6H), 1.88–1.97 (m, 2H).

c)(3-{3-Methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amine

In a similar manner as exemplified for example 284, part c), 726 mg of4-(3-dimethylamino-propoxy)-2-methoxy benzoic acid hydrazide wasconverted into 720 mg(3-{3-methoxy-4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenoxy}-propyl)-dimethyl-amineas the free base.

¹H NMR (CHCl₃-d1) δ 7.80 (d, 1H, J=8.85 Hz), 7.24 (t, 2H, J=7.43 Hz),6.92 (t, 1H, J=7.43 Hz), 6.86 (d, 2H, J=8.85 Hz), 6.52–6.58 (m, 2H),4.17 (t, 2H, J=6.37 Hz), 4.06 (t, 2H, J=6.37 Hz), 4.00 (s, 2H), 3.89 (s,3H), 3.04 (t, 2H, J=6.37 Hz), 2.44 (t, 2H, J=7.08 Hz), 2.24 (s, 6H),1.91–2.00 (m, 2H).

Example 293 Preparation of1-methyl-4-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-piperazine;maleic acid salt

a) 6-(4-Methyl-piperazin-1-yl)-nicotinic acid methyl ester

803.7 mg (4.69 mmol) of methyl 6-chloronicotinate, 570 uL (5.16 mmol) ofN-methyl-piperidine, and 980 uL of diisopropylethylamine were and heatedto 50° C. in 10 mL of dry DMF for 24 h. The mixture was then cooled anddiluted with about 100 mL of ethylacetate which was then washed withabout 30 mL of 2N NaOH, about 30 mL of brine. The organic fraction wasdried over magnesium sulfate and then evaporated under reduced pressureto yield 1.1 gm of 6-(4-methyl-piperazin-1-yl)-nicotinic acid methylester as a yellow solid.

¹H NMR (CHCl₃-d1) δ 8.76 (d, 1H, J=2.12 Hz), 7.99 (dd, 1H, J=8.85, 2.48Hz), 6.56 (d, 1H, J=9.20 Hz), 3.84 (s, 3H), 3.68 (t, 4H, J=4.95 Hz),2.48 (t, 4H, J=4.95 Hz), 2.32 (s, 3H).

b) 6-(4-Methyl-piperazin-1-yl)-nicotinic acid hydrazide

In a similar manner as exemplified for example 291, part b), 1.05 gm of6-(4-methyl-piperazin-1-yl)-nicotinic acid methyl ester was convertedinto 1.05 gm of 6-(4-methyl-piperazin-1-yl)-nicotinic acid hydrazide asa waxy solid

¹H NMR (CHCl₃-d1) δ 8.50 (d, 1H, J=2.12 Hz), 7.84 (dd, 1H, J=8.85, 2.48Hz), 7.13 (bs, 1H), 6.60 (d, 1H, J=8.85 Hz), 4.02 (bs, 1H), 3.65 (t, 4H,J=5.81 Hz), 2.48 (t, 4H, J=4.95 Hz), 2.32 (s, 3H).

c)1-Methyl-4-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-piperazine;maleic acid salt

In a similar manner as exemplified for example 284, part c), 1.00 gm of6-(4-methyl-piperazin-1-yl)-nicotinic acid hydrazide was converted into1.00 gm of1-methyl-4-{5-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-piperazine;maleic acid salt as a white solid. mp=146–147° C.

¹H NMR (CH₃OH-d4) δ 8.74 (d, 1H, J=1.77 Hz), 8.09 (dd, 1H, J=9.20, 2.12Hz), 7.20 (t, 2H, J=8.14 Hz), 7.02 (d, 1H, J=8.85 Hz), 6.83–6.90 (m,3H), 6.23 (s, 2H), 4.17 (t, 2H, J=6.01 Hz), 4.13 (s, 2H), 3.33 (bs, 2H),3.03 (t, 2H, J=6.37 Hz), 2.91 (s, 3H). Anal. Calcd for C₂₅H₂₉N₅O₆S: C,56.91; H, 5.54; N, 13.27. Found C, 56.85; H, 5.36; N, 13.19.

Example 294 Preparation of1-methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperazine;maleic acid salt

a) 4-(4-Methyl-piperazin-1-yl)-benzoic acid hydrazide

800 mg (3.41 mmol) of methyl 4-(4-methylpiperazino)benzenecarboxylate, 3mL of hydrazine hydrate and 6 mL of ethanol were heated at 55° C. for 24hours at which time another 1 mL of hydrazine hydrate was added andheating was continued for another 24 hours. The solvents were thenremoved under reduced pressure and the resultant solid was purified onabout 100 gm of silica gel using a 0 to 10% gradient of a 2N ammonia inmethanol mixture in methylene chloride, and then 1.8 L of a 10% 2Nammonia in methanol mixture in methylene chloride to give 620 mg of4-(4-methyl-piperazin-1-yl)-benzoic acid hydrazide as a yellow waxysolid.

¹H NMR (CHCl₃-d1) δ 7.63 (d, 2H, J=9.20 Hz), 7.27 (bs, 1H), 6.86 (d, 2H,J=9.20 Hz), 4.03 (bs, 2H), 3.28 (t, 4H, J=4.95 Hz), 2.53 (t, 4H, J=4.95Hz), 2.32 (s, 3H).

b)1-Methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperazine;maleic acid salt

In a similar manner as exemplified in example 284, part c), 621 mg of4-(4-methyl-piperazin-1-yl)-benzoic acid hydrazide was converted into1.08 gm of1-methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperazine;maleic acid salt as a yellow solid. mp=151–152° C.

¹H NMR (CHCl₃-d1) δ 7.93 (d, 2H, J=8.85 Hz), 7.25 (t, 2H, J=8.49 Hz),6.90–6.98 (m, 3H), 6.87 (d, 2H, J=7.78 Hz), 6.27 (s, 2H), 4.18 (t, 2H,J=6.19 Hz), 4.02 (s, 2H), 3.2–3.9 (bs, 6H), 3.03 (t, 2H, J=6.19 Hz),2.86 (s, 3H).

Example 295 Preparation of5-(2-Phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoxazole

a) 4-(Tetrahydro-pyran-2-yloxy)-benzaldehyde

A round bottom flask was charged with 4-hydroxy-benzaldehyde (1.32 g,10.8 mmol), evacuated by vacuum pump and filled with N₂. The aldehydewas diluted with CH₂Cl₂ (15 mL) giving a cloudy mixture.3,4-Dihydro-2H-pyran (1.5 mL, 16.2 mmol) was added by syringe,pyridinium p-toluenesulfonate (0.27 g, 1.1 mmol) was added neat and thereaction stirred at rt under N₂ for one hour. A reflux condensor wasattached and the mixture stirred in a 45° C. oil bath overnight. Thereaction was quenched with sat. aq. NaHCO₃, the organic layer removedand the aqueous phase extracted with EtOAc (2×). The combined organicswere dried over MgSO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane0%-80%) to give the title compound (0.87 g, 39%): ¹H NMR (CDCl₃): δ 9.88(s, 1H), 7.82 (ap d, J=8.8 Hz, 2H), 7.15 (ap d, J=8.8 Hz, 2H), 5.54 (t,J=3.1 Hz, 1H), 3.89–3.81 (m, 1H), 3.67–3.60 (m, 1H), 2.08–1.96 (m, 1H),1.93–1.87 (m, 2H), 1.79–1.52 (m, 3H); TLC (30% EtOAc/hexane) Rƒ 0.36.

b) 4-(Tetrahydro-pyran-2-yloxy)-benzaldehyde oxime

To a solution of 4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (0.87 g, 4.2mmol) in EtOH was added NaOAc³⁰ 3H₂O (2.3 g, 16.9 mmol) andhydroxylamine hydrochloride (0.44 g, 6.3 mmol). The mixture was stirredat rt for 30 min, concentrated, diluted with sat. aq. NaHCO₃, andextracted with EtOAc (3×). The combined organics were dried over MgSO₄,filtered and concentrated. The crude product was purified by flashchromatography on silica gel (gradient EtOAc/Hexane 0%–80%) to givepredominantly one diastereomer as the title compound (0.63 g, 68%): ¹HNMR (CDCl₃): δ 8.08 (s, 1H), 7.50 (ap d, J=8.9 Hz, 2H), 7.06 (ap d,J=8.9 Hz, 2H), 5.46 (t, J=3.2 Hz, 1H), 3.92–3.85 (m, 1H), 3.65–3.59 (m,1H), 2.07–1.96 (m, 1H), 1.91–1.85 (m, 2H), 1.77–1.57 (m, 3H); TLC (30%EtOAc/hexane) Rƒ 0.29.

c) 4-(Tetrahydro-pyran-2-yloxy)-benzaldehyde chloro-oxime

To a solution of 4-(Tetrahydro-pyran-2-yloxy)-benzaldehyde oxime (2.23g, 10.1 mmol) in DMF at rt was added in one portion N-chlorosuccinimide(1.88 g, 14.1 mmol). After heating with a heat gun for 1 minute, thereaction went from a clear colorless solution to a clear light yellowsolution. The reaction was stirred for 78 hours at rt, quenched with 50%sat. aq. NaCl, extracted with ether (3×), dried over MgSO₄, filtered andconcentrated. The crude product was azeotroped with xylenes (2×) on theRotovap to remove DMF and purified by flash chromatography on silica gel(gradient EtOAc/Hexane 0%–70%) to give the title compound contaminatedwith starting material (1.25 g): ¹H NMR (CDCl₃): δ 7.49–7.41 (m, 2H),7.12–7.05 (m, 2H), 5.47 (ap q, 4H), 3.93–3.80 (m, 1H), 2.05–1.96 (m,1H), 1.92–1.85 (m, 2H), 1.75–1.54 (m, 3H).

d) 5-Chloromethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole

To a solution of 4-(tetrahydro-pyran-2-yloxy)-benzaldehyde chloro-oxime(1.25 g, 4.9 mmol) and 3-chloro-propyne (0.42 mL, 5.9 mmol) in ethylacetate, DIPEA (1.02 mL, 5.9 mmol) was added slowly at rt, giving acloudy suspension. The reaction was stirred for 16 hours then quenchedwith 80% sat. aq. NH₄Cl. After removal of the organic phase, the aqeuousphase was extracted with EtOAc (2×) and the combined organics dried overMgSO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (gradient EtOAc/Hexane 0%–70%) givingthe title compound as the only regioisomer (1.10 g): ¹H NMR (CDCl₃):δ7.72 (ap d, J=8.9 Hz, 2H), 7.45 (m, 2H), 7.14–7.07 (m, 2H), 6.58 (s,1H), 5.50–5.45 (m, 1H), 4.65 (s, 2H), 3.93–3.85 (m, 1H), 3.66–3.60 (m,1H), 2.07–1.98 (m, 1H), 1.92–1.86 (m, 2H), 1.77–1.59 (m, 3H); TLC (30%EtOAc/Hexane) Rf 0.36.

e)5-(2-Phenoxy-ethylsulfanylmethyl)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole

An oven-dried round bottom flask was charged with NaH (60% in mineraloil, 0.13 g, 3.1 mmol), evacuated with a vacuum pump and filled with N₂.After dilution with anhydrous THF (10 mL), the flask was set in anice-water bath and 2-phenoxy-ethanethiol (0.32 g, 2.09 mmol) in THF (5mL) added slowly by syringe under N₂. The reaction was stirred 30minutes at 0° C., then removed from the bath and stirred 20 minutes atambient temperature.5-Chloromethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole (0.68g, 2.30 mmol) in THF (10 mL) was added by syringe, causing the reactionto change from colorless to yellow after 30 minutes. The reaction wasstirred overnight then quenched with H₂O, diluted with hexane and theorganic phase removed. The aqueous phase was extracted with EtOAc (2×),the combined organic phases were dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (gradient EtOAc/Hexane 10%–50%) to give the title compound(0.51 g): ES-MS 412.1 (M+1), ¹H NMR (CDCl₃): δ 7.70 (ap d, J=8.9 Hz,2H), 7.31–7.25 (m, 2H), 7.11 (ap d, J=8.9 Hz, 2H), 6.96 (ap t, 1H), 6.90(ap d, J=8.1 Hz, 2H), 6.44 (s, 1H), 5.49 (t, J=3.3 Hz, 1H), 4.20 (t,J=6.2 Hz, 2H), 3.96 (s, 2H), 3.94–3.86 (m, 1H), 3.66–3.60 (m, 1H), 2.99(t, J=6.2 Hz, 2H), 2.08–1.98 (m, 1H), 1.92–1.86 (m, 2H), 1.77–1.58 (m,3H).

f) 4-[5-(2-Phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-phenol

To a mixture of5-(2-phenoxy-ethylsulfanylmethyl)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole(0.51 g, 1.23 mmol) in ethanol was added pyridinium p-toluenesulfonate(0.03 g, 0.12 mmol). A reflux condensor was attached and the reactionstirred in a 50° C. oil bath for 3 hours. The mixture was concentratedand the crude product purified by flash chromatography on silica gel(10% EtOAc/Hexane) to give the title compound as a clear, colorless oil(0.39 g, 97%): ES-MS 328.1 (M+1), ¹H NMR (CDCl₃): δ 7.66 (ap d, J=8.7Hz, 2H), 7.30–7.25 (m, 2H), 6.99–6.88 (m, 5H), 6.44 (s, 1H), 5.33 (br s,1H), 4.21 (t, J=6.2 Hz, 2H), 3.96 (s, 2H), 3.00 (t, J=6.2 Hz, 2H).

g)5-(2-Phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoxazole

An oven-dried round bottom flask was charged with4-[5-(2-phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-phenol (0.282 g,0.86 mmol), evacuated with a vacuum pump and filled with N₂. AnhydrousDMF (5 mL) was added by syringe and after dissolution of the phenol thereaction was set in an ice-water bath and stirred 5 minutes. NaH (60% inmineral oil, 0.09 g, 2.24 mmol) was added neat. The mixture was stirred5 minutes at 0° C., then removed from the bath and allowed to warn tort. 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (0.176 g, 1.03 mmol)was added neat. A reflux condensor was attached and the mixture stirred6 hours in a 50° C. oil bath. The reaction was quenched with 50% sat.aq. NaHCO₃ and the mixture extracted with EtOAc (3×). The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated, then azeotroped with xylenes on the Rotovap (2×) to removeDMF. The crude product was purified by flash chromatography on silicagel (gradient EtOAc/Hexane 30%–85%, 2N NH₃ in MeOH/EtOAc 5%) thencrystallized in CH₂Cl₂/Ether/Hexane to give the title compound as finewhite crystals (0.197 g, 54%): ES−MS 425.1 (M+1), ¹H NMR (CDCl₃): δ 7.69(ap d, J=8.8 Hz, 2H), 7.30–7.25 (m, 2H), 7.00–6.94 (m, 3H), 6.91–6.88(m, 2H), 6.44 (s, 1H), 4.22–4.17 (m, 4H), 3.96 (s, 2H), 3.02–2.93 (m,4H), 2.70 (br s, 4H), 1.88–1.83 (m, 4H). Anal. calcd. for C₂₄H₂₈N₂O₃S:C, 67.90; H, 6.65; N, 6.60. Found: C, 67.97; H, 6.61; N, 6.67.

Example 296 Preparation of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol

a) 4-(Tetrahydro-pyran-2-yloxy)-benzonitrile

A solution of 4-cyanophenol (2.73 g, 22.9 mmol) in CH₂Cl₂ (15 mL) wastreated with 3,4-dihydro-2H-pyran (4.19 mL, 45.8 mmol) and pyridiniump-toluenesulfonate (0.57 g, 2.29 mmol). A reflux condensor was attachedand the mixture stirred in a 50° C. oil bath for 3 hours. Afterconcentrating on the RotoVap, the crude product was purified by flashchromatography on silica gel (gradient EtOAc/Hexane 0%–50%) to give aclear oil, which crystallized neat to give the title compound as finewhite crystals (4.35 g, 93%): ¹H NMR (CDCl₃): δ 7.57 (dt, J=8.7, 2.4 Hz,2H), 7.10 (dt, J=8.7, 24 Hz, 2H), 5.49 (t, J=3.0 Hz, 1H), 3.85–3.77 (m,1H), 3.65–3.59 (m, 1H), 2.04–1.92 (m, 1H), 1.90–1.84 (m, 2H), 1.77–1.50(m, 3H); TLC (30% EtOAc/Hexane) Rf 0.47.

b) N-{Amino-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-methyl}-hydroxylamine

A CEM reaction vial (for microwave reactions) with stir-bar was chargedwith 4-(tetrahydro-pyran-2-yloxy)-benzonitrile (3.14 g, 15.4 mmol). Thenitrile was diluted with anhydrous ethanol (25 mL) and treated withhydroxylamine hydrochloride (1.61 g, 23.2 mmol) and ground NaOH (0.93 g,23.2 mmol). A septum was attached and the reaction microwaved in the CEMDiscover reactor at 80° C. for 40 minutes (cooling on, average power 40watts). The mixture was concentrated, diluted with H₂O, and extractedwith EtOAc (3×). The combined organics were washed with brine, driedover MgSO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (gradient EtOAc/Hexane 20%–100%) togive the title compound as a white foam (1.89 g, 52%): ES-MS 237.1(M+1); ¹H NMR (CDCl₃): δ 7.55 (dt, J=8.8, 2.5 Hz, 2H), 7.06 (dt, J=8.8,2.5 Hz, 2H), 5.46 (t, J=3.0 Hz, 1H), 4.85 (br s, 2H), 3.92–3.85 (m, 1H),3.65–3.58 (m, 1H), 2.05–1.96 (m, 1H), 1.91–1.85 (m, 2H), 1.76–1.57 (m,3H).

c) (2-Phenoxy-ethylsulfanyl)-acetyl chloride

An oven-dried round-bottom flask with stir-bar was charged with(2-phenoxy-ethylsulfanyl)-acetic acid (Maybridge, 5.57 g, 26.2 mmol).The flask was evacuated and filled with N₂. Anhydrous CH₂Cl₂ (20 mL) andDMF (4 drocl) was added by syringe and the flask was set in an ice-waterbath. Oxalyl chloride (2M/CH₂Cl₂, 26.2 mL, 52.4 mmol) was added dropwiseby syringe and the reaction stirred for 2 hours while the bath expired.The reaction mixture was concentrated then azeotroped with xylenes(remove DMF) on the RotoVap to give the title compound as a brown oil(6.57 g, 109%). ¹H NMR (CDCl₃): δ 7.32–7.27 (m, 2H), 7.01–6.96 (m, 1H),6.92–6.88 (m, 2H), 4.23 (t, 15.8 Hz, 2H), 3.91 (s, 2H), 3.05 (t, J=5.8Hz, 2H).

d) 4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol

In a CEM reaction vial with stir-bar a solution ofN-{Amino-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-methyl}-hydroxylamine(1.52 g, 6.43 mmol) in pyridine was treated with(2-phenoxy-ethylsulfanyl)-acetyl chloride (1.78 g, 7.72 mmol). Thereaction was stirred at rt for 15 minutes, then microwaved in the CEMDiscover reactor at 65° C. (cooling on) for 20 minutes and 80° C.(cooling on) for 30 minutes. The reaction mixture was transferred to arb flask, concentrated then azeotroped with heptane on the RotoVap (2×)to remove pyridine. The mixture was dissolved in ethanol, transferred toa CEM reaction vial and treated with pyridinium p-toluenesulfonate (0.16g, 0.64 mmol). A septum was attached and the reaction microwaved at 55°C. (cooling on) for 10 minutes then 75° C. (cooling on) for 10 minutes.The mixture was concentrated on the RotoVap and purified by flashchromatography on silica gel (gradient EtOAc/Hexane 0–70%) to give thetitle compound as a clear yellow oil (1.37 g, 65%): ES-MS 329.1 (M+1),¹H NMR (CDCl₃): δ 7.96 (dt, J=8.9, 2.4 Hz, 2H), 7.30–7.25 (m, 2H),6.98–6.88 (m, 5H), 5.49 (br s, 1H), 4.24 (t, J=6.2 Hz, 2H), 4.05 (s,2H), 3.11 (t, J=6.2 Hz, 2H).

Example 2971-(2-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-ethyl)-piperidinehydrochloride

In oven-dried round bottom flask was charged with4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol(0.258 g, 0.78 mmol), evacuated with a vacuum pump and filled with N₂.Anhydrous DMF (5 mL) was added by syringe and after dissolution of thephenol the reaction was set in an ice-water bath. NaH (60% in mineraloil, 0.08 g, 2.0 mmol) was added neat. The mixture was stirred 1 minuteat 0° C., removed from the bath and stirred 5 minutes at rt.1-(2-Chloro-ethyl)-piperidine hydrochloride (0.173 g, 0.94 mmol) wasadded neat, a reflux condenser was attached and the mixture stirred 1.5hours in a 50° C. oil bath. The reaction was quenched with 50% sat. aq.NaHCO₃ and extracted with EtOAc (3×). The combined organics were washedwith brine, dried over MgSO₄, filtered and concentrated, then azeotropedwith xylenes on the Rotovap (2×) to remove DMF. The crude product waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane30%–85%, 2N NH₃ in MeOH/EtOAc 5%) to give the free base as a clear oil.The free base was dissolved in ethanol and treated with 1M HCl/ether togive the title compound as white crystals. ES-MS 440.1 (M+1), ¹H NMR(DMSO d6): δ 10.56 (s, 1H), 7.94 (dt, J=8.8, 2.4 Hz, 2H), 7.25 (ap t,2H), 7.16 (dt, J=8.8 Hz, 2.4 Hz, 2H), 6.94–6.89 (m, 3H), 4.49 (t, J=5.0Hz, 2H), 4.26 (s, 2H), 4.20 (t, J=6.3 Hz, 2H), 3.53–3.45 (m, 4M), 3.06(t, J=6.3 Hz, 2H), 3.03–2.94 (m, 2H), 1.84–1.76 (m, 4H), 1.69 (m, 1H),1.44–1.33 (m, 1H). Anal. calcd. for C₂₄H₃₀ClN₃O₃S: C, 60.55; H, 6.35; N,8.83. Found: C, 59.91; H, 5.90; N, 8.57.

Example 298Dimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4)oxadiazol-3-yl]-phenoxy}-ethyl)-aminehydrochloride

A CEM reaction vessel was charged with NaH (60% in mineral oil, 0.15 g,3.8 mmol). The vessel was capped with a septum and evacuated by a vacuumpump. DMF (3 mL) was added by syringe, the vessel filled with N₂ and setin an ice-water bath.4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol(0.422 g, 1.28 mmol) in DMF (2 mL) was added dropwise by syringe. Themixture was stirred 5 minutes at 0° C., removed from the bath andstirred 15 minutes at rt. The septum was removed,(2-chloro-ethyl)-dimethyl-amine hydrochloride (0.222 g, 1.54 mmol) wasadded neat, a new septum cap was attached and the reaction stirred 5minutes at rt. The reaction was microwaved in the CEM Discover reactorat 70° C. (cooling on) for 20 minutes, then quenched with H₂O andextracted with EtOAc (3×). The combined organics were washed with brine,dried over MgSO₄, filtered and concentrated, then azeotroped withxylenes on the Rotovap (2×) to remove DMF. The crude product waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane30%–85%, 2N NH₃ in MeOH/EtOAc 5%). The free base was dissolved inethanol and treated with 1M HCl/ether to give the title compound aswhite crystals (0.230 g, 41%). ES-MS 400.1 (M+1), ¹H NMR (DMSO d₆): δ10.26 (s, 1H), 7.95 (dt, J==8.8, 2.5 Hz, 2H), 7.25 (ap t, 2H), 7.16 (dt,J=8.8 Hz, 2.5 Hz, 2H), 6.94–6.89 (m, 3H), 4.43 (t, J=5.0 Hz, 2H), 4.27(s, 2H), 4.20 (t, J=6.3 Hz, 2H), 3.52 (t, J=5.0 Hz, 2H), 3.06 (t, J=6.3Hz, 2H), 2.85 (s, 6H). Anal. calcd. for C₂₁H₂₆ClN₃O₃S: C, 57.85; H,6.01; N, 9.64. Found: C, 57.72; H, 5.90; N, 9.46.

e)5-(2-Phenoxy-ethylsulfanylmethyl)-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]oxadiazolehydrochloride

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol usinga method similar to that described fordimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-ethyl)-aminehydrochloride: ES-MS 426.1 (M+1), ¹H NMR (DMSO d₆): δ 10.39 (s, 1H),7.95 (dt, J=8.8, 2.5 Hz, 2H), 7.25 (ap t, 2H), 7.15 (dt, J=8.8 Hz, 2.5Hz, 2H), 6.94–6.89 (m, 3H), 4.40 (t, J=5.0 Hz, 2H), 4.26 (s, 2H), 4.19(t, J=6.3 Hz, 2H), 3.63–3.54 (m, 41, 3.16–3.03 (m, 4H), 2.05–1.96 (m,2H), 1.94–1.83 (m, 2H). Anal. calcd. for C₂₃H₂₈ClN₃O₃S: C, 59.79; H,6.11; N, 9.09. Found: C, 59.55; H, 6.15; N, 8.94.

e)3-{4-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazolehydrochloride

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol usinga method similar to that described fordimethyl-(2-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-ethyl)-aminehydrochloride: ES-MS 440.1 (M+1), ¹H NMR (DMSO d₆): δ 10.69 (m, 1H),7.91 (ap t, 2H), 7.25 (ap t, 2H), 7.13–7.08 (m, 2H), 6.94–6.88 (m, 3),4.26 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.48–3.29 (m, 1H), 3.18–2.99 (m,4H), 2.82–2.73 (m, 3H), 2.46–1.69 (m, 7H).

Example 299 Preparation of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide

a) 4-Hydroxyaminomethyl-benzoic acid methyl ester

To a solution of 4-formyl-benzoic acid methyl ester (4.18 g, 25.5 mmol)in EtOH was added NaOAc·3H₂O (6.93 g, 50.9 mmol) and hydroxylaminehydrochloride (2.65 g, 38.2 mmol). The mixture was stirred at rt for 1hour, concentrated on the Rotovap, diluted with H₂O, and extracted withEtOAc (3×). The combined organics were dried over MgSO₄, filtered andthe solvent removed under vacuum to give a white residue as crude (4.02g, 88%): ¹H NMR (CDCl₃): δ 8.17 (s, 1H), 8.05 (ap d, J=8.5 Hz, 2H), 7.65(ap d, J=8.5 Hz, 2H), 3.94 (s, 3H); TLC (20% EtOAc/Hexane) Rf 0.18

b) 4-(Chloro-hydroxyamino-methyl)-benzoic acid methyl ester

To a solution of 4-hydroxyaminomethyl-benzoic acid methyl ester (4.02 g)in DMF at rt was added in five portions N-chlorosuccinimide (4.24 g,31.7 mmol). After addition of the first portion, the reaction was heatedwith a heat gun for 10 seconds, giving a cloudy mixture. The remainingportions were added over 2 minutes. The reaction was stirred for 1 hourat rt, quenched with 70% sat. aq. NaCl, extracted with ether (3×), driedover MgSO₄, filtered and concentrated. The crude product was azeotropedwith xylenes (2×) to remove residual DMF, giving a white residue ascrude product (5.56 g): ¹H NMR (CDCl₃): δ 9.04 (br s, 1H), 8.05 (ap d,J=8.8 Hz, 2H), 7.92 (ap d, J=8.8 Hz, 2H), 3.94 (s, 3H); TLC (20%EtOAc/Hexane) Rf 0.18

c) 4-(5-Chloromethyl-isoxazol-3-yl)-benzoic acid methyl ester

To a solution of 4-(chloro-hydroxyimino-methyl)-benzoic acid methylester (1.14 g, 5.35 mmol) and 3-chloro-propyne (0.46 mL, 6.42 mmol) inethyl acetate TEA (0.89 mL, 6.42 mmol) was added slowly at rt, giving acloudy mixture. The reaction was stirred for 16 hours then quenched with75% sat. aq. NH₄Cl. After removal of the organic phase, the aqeuousphase was extracted with EtOAc (2×) and the combined organics dried overMgSO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (gradient EtOAc/Hexane 0%–80%) givingthe title compound as the only regioisomer (0.84 g, 62%). The structureof the regioisomer was confirmed by 1-D NOESY analysis: ES-MS 252.0(M+1), ¹H NMR (CDCl₃): δ 8.13 (ap d, J=8.7 Hz, 2H), 7.88 (ap d, J=8.7Hz, 2H), 6.69 (s, 1H), 4.68 (d, J=0.8 Hz, 2H), 3.96 (s, 3H).

d) 4-[5-(2-Phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-benzoic acidmethyl ester

An oven-dried round bottom flask was charged with NaH (60% in mineraloil, 0.10 g, 2.5 mmol), evacuated with a vacuum pump and filled with N₂.After dilution with anhydrous THF (10 mL), the reaction was set in anice-water bath and 2-phenoxy-ethanethiol (0.25 g, 1.6 mmol) in THF (20mL) added slowly by syringe. The reaction was stirred 30 minutes at 0°C., then removed from bath and allowed to warm to rt.4-(5-Chloromethyl-isoxazol-3-yl)-benzoic acid methyl ester (0.45 g, 1.8mmol) in THF (10 mL) was added by syringe, giving a cloudy yellowmixture. The reaction was stirred overnight then neutralized with 0.25 NHCl and extracted with EtOAc (3×). The combined organic phases weredried over MgSO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane30%–85%, MeOH/EtOAc 5%) to give the methyl ester of the title compound(0.16 g) and the title compound (0.20 g): ES-MS 356.0 (M+1), ¹H NMR(CDCl₃): δ 13.14 (br s, 1H), 8.07–7.93 (m, 5H), 7.29–7.21 (m, 2H), 7.01(s, 1H), 6.94–6.88 (m, 2H), 4.16 (t, J=6.4 Hz, 2H), 4.11 (s, 2H), 2.96(t, J=6.4 Hz, 2H).

e)4-[5-(2-Phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide

To a mixture of4-[5-(2-phenoxy-ethylsulfanylmethyl)-isoxazol-3-yl]-benzoic acid (0.20g, 0.55 mmol) in CH₂Cl₂ was added neat HOBt (0.11 g, 0.83 mmol),EDCI-HCl (0.16 g, 0.83 mmol), and DIPEA (0.19 mL, 1.11 mmol) at rt.2-Pyrrolidin-1-yl-ethylamine (0.11 mL, 0.83 mmol) was added by syringeand the reaction stirred 1 hour. The reaction was quenched with 50% sat.aq. NaHCO₃ and the organic phase removed. The aqueous phase wasextracted with EtOAc (2×) and the combined organics dried over MgSO₄,filtered and concentrated. The crude product was purified by radialchromatography on silica gel (gradient EtOAc/Hexane 30%–85%, 2N NH₃ inMeOH/EtOAc 5%–20%) then repurified by RP-HPLC to give the TFA salt. Thesalt was free-based with NaHCO₃ and crystallized in CH₂Cl₂/ether/hexane.The title compound was recovered as fine white crystals (0.029 g): ES-MS452.3 (M+1), ¹H NMR (CDCl₃): δ 7.91–7.82 (m, 4H), 7.31–7.25 (m, 2H),6.96 (ap t, J=7.5 Hz, 1H), 6.90 (ap d, J=8.0 Hz, 2H), 6.67 (s, 1H), 4.22(t, J=6.1 Hz, 2), 3.99 (s, 2H), 3.64 (ap q, 2H), 3.01 (t, J=6.1 Hz, 2H),2.86 (br s, 2H), 2.74 (br s, 4H), 1.89 (br s, 4H). Anal. calcd. forC₂₅H₂₉N₃O₃S: C, 66.49; H, 6.47; N, 9.30. Found: C, 65.04; H, 6.20; N,9.10.

Example 300 Preparation ofDimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-isoxazol-5-ylmethyl)-amine

a) 4-(Hydroxyimino-methyl)-benzoic acid methyl ester

To a solution of 4-Formyl-benzoic acid methyl ester (Aldrich, 4.94 g,30.1 mmol) in EtOH was added NaOAc¹⁹ 3H₂O (8.19 g, 60.2 mmol) andhydroxylamine hydrochloride (3.14 g, 45.1 mmol). The mixture was stirredat rt for 90 minutes, concentrated on the Rotovap, diluted with H₂O, andextracted with EtOAc (3×). The combined organics were dried over MgSO₄,and the solvent removed under vacuum to give a white residue as crude(5.17 g): ¹H NMR (CDCl₃): δ 8.17 (s, 1H), 8.06 (ap d, J=8.4 Hz, 2), 7.85(br s, 1H), 7.65 (ap d, J=8.4 Hz, 2H), 3.93 (s, 3H).

b) 4-(Chloro-hydroxyimino-methyl)-benzoic acid methyl ester

To a solution of 4-(Hydroxyimino-methyl)-benzoic acid methyl ester (5.17g, 28.8 mmol) in DMF at rt was added in two portions N-chlorosuccinimide(4.24 g, 31.7 mmol). After addition of first portion, the reaction washeated with a heat gun for 10 seconds to give a cloudy mixture. Theremaining portion was added and reaction became hotter (exotherm) forseveral minutes then slowly cooled. The reaction was stirred for 15minutes at rt, quenched with 50% sat. aq. NaCl, extracted with ether(3×), dried over MgSO₄, filtered and concentrated. The crude product wasazeotroped with xylenes (2×) to remove DMF, giving a white residue asthe title compound (7.17 g): ES-MS 195.1 (M+1), ¹H NMR (CDCl₃): δ 9.10(s, 1H), 8.06 (ap d, J=8.5 Hz, 2H), 7.93 (ap d, J=8.4 Hz, 2H), 3.93 (s,3H).

c) 4-(5-Diethoxymethyl-isoxazol-3-yl)-benzoic acid methyl ester

To a solution of 4-(Chloro-hydroxyimino-methyl)-benzoic acid methylester (7.17 g, 28.8 mmol) and 3,3-diethoxy-propyne (4.95 mL, 34.6 mmol)in ethyl acetate, TEA (4.82 mL, 34.6 mmol) was added slowly over 20minutes at rt, giving a thick suspension. The reaction was stirred for16 hours then quenched with H₂O. After removal of the organic phase, theaqeuous phase was extracted with CH₂Cl₂ (2×) and the combined organicsdried over MgSO₄, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane10%–85%, 5% MeOH/EtOAc) giving the title compound (4.26 g): ES-MS 306.2(M+1), ¹H NMR (CDCl₃): δ 8.12 (ap d, 2H), 7.89 (ap d, 2H), 6.71 (s, 1H),5.69 (s, 1H), 3.69 (m, 4H), 1.28 (t, J=7.0 Hz, 6H).

d) 4-(5-Diethoxymethyl-isoxazol-3-yl)-benzoic acid hydrazide

4-(5-Diethoxymethyl-isoxazol-3-yl)-benzoic acid methyl ester (4.26 g,13.9 mmol) was diluted with isopropanol (25 mL) and hydrazine (2.0 mL,70 mmol) was added by syringe under N₂. The mixture was refluxed in a100° C. oil bath for 16 hours. The reaction was concentrated, thendiluted with CH₂Cl₂ and concentrated (2×) on Rotovap, then placed onhigh vacuum for 2 hours, giving the title compound as a thick oil (4.24g): ¹H NMR (DMSO-d₆): δ 9.88 (br s, 1H), 7.95 (m, 41H), 7.14 (s, 1H),5.80 (s, 1H), 3.63 (q, J=7.1 Hz, 4H), 3.32 (br s, 2H), 1.19 (t, J=7.1Hz, 6H).

e) 4-(5-Diethoxymethyl-isoxazol-3-yl)-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

A mixture of (2-phenoxy-ethylsulfanyl)-acetic acid (Maybridge, 2.95 g,13.9 mmol) and N,N′-carbonyldiimidazole (2.25 g, 13.9 mmol) in THF/MeCN1:1 (15 mL) was heated at 60° C. for one hour, then allowed to cool tort. 4-(5-Diethoxymethyl-isoxazol-3-yl)-benzoic acid hydrazide (4.24 g,13.9 mmol) was added in one portion and the mixture stirred at rt underN₂ for 16 hours, then stirred at 50° C. for 4 hours. The reaction waspoured into H₂O and extracted with EtOAc (1×) and CH₂Cl₂ (2×). Thecombined organics were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by flash chromatography on silica gel(gradient EtOAc/Hexane 10%–85%, MeOH/EtOAc 5%–10%) to give the titlecompound (2.75 g): ES-MS 500.2 (M+1), ¹H NMR (CDCl₃): δ 9.54 (ap d, 1H),9.06 (ap t, 1H), 7.84 (m, 4H), 7.30–7.23 (m, 2H), 6.98–6.87 (m, 3H),6.69 (s, 1H), 5.69 (s, 1H), 4.25 (t, J=5.8 Hz, 2H), 3.69 (m, 4H), 3.51(s, 2H), 3.10 (t, J=5.8 Hz, 2H), 1.29 (t, J=7.0 Hz, 6H).

f)2-[4-(5-Diethoxymethyl-isoxazol-3-yl)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

A mixture of 4-(5-diethoxymethyl-isoxazol-3-yl)-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (2.75 g, 5.5 mmol),triphenylphosphine (1.73 g, 6.6 mmol), and TEA (2.67 mL, 19.3 mmol) inTHF was treated with carbon tetrabromide (2.19 g, 19.3 mmol) and stirredat rt under N₂. After 1 hour, the reaction was heated to 50° C. andstirred 3 hours. The reaction was removed from heat and additionaltriphenylphosphine (0.29 g, 1.1 mmol) and carbon tetrabromide (0.36 g,1.1 mmol) was added, then returned to heat and stirred for 16 hours. Themixture was concentrated, neutralized with sat. aq. NH₄Cl and extractedwith EtOAc (3×), dried over MgSO₄, filtered and concentrated. Theresulting crude was purified by flash chromatography on silica gel(gradient CH₂Cl₂/Hexane 50%–100%, MeOH/CH₂Cl₂ 2%–110%) then repurified(gradient EtOAc/Hexane 10%–50%) to give the title compound as anoff-white residue (0.80 g): ES-MS 482.2 (M+1), ¹H NMR (CDCl₃): δ 8.12(ap d, J=8.5 Hz, 2H), 7.96 (ap d, J=8.5 Hz, 2H), 7.29–7.25 (m, 2H),6.98–6.88 (m, 3H), 6.73 (s, 1H), 5.72 (s, 1H), 4.23 (t, J=6.1 Hz, 2H),4.09 (s, 2H), 3.70 (m, 4H), 3.08 (t, J=6.1 Hz, 2H), 1.30 (t, J=7.0 Hz,6H).

g)3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-isoxazole-5-carbaldehyde

To a solution of2-[4-(5-diethoxymethyl-isoxazol-3-yl)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(0.80 g, 1.7 mmol) in acetic acid/H₂O (4:1, 25 mL) was added slowly 1 Naq. HCl (3 mL), giving a thick suspension. The mixture was stirred 5minutes at rt, concentrated, diluted with acetone and concentrated (2×),then placed on high vacuum to give the title compound: ES-MS 482.2 (M+33consistent with aldehyde), ¹H NMR (CDCl₃): δ 10.06 (s, 1), 8.16 (ap d,J=8.4 Hz, 2H), 7.98 (ap d, J=8.4 Hz, 2H), 7.35 (s, 1H), 7.30–7.24 (m,2H), 6.98–6.87 (m, 3H), 4.23 (t, J=6.2 Hz, 2H), 4.10 (s, 2H), 3.08 (t,J=6.2 Hz, 2H).

h)Dimethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-isoxazol-5-ylmethyl)-amine

To a solution of3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-isoxazole-5-carbaldehyde(0.14 g, 0.34 mmol) in 1,2-dichloroethane was added dimethylamine (2M/MeOH, 0.7 mL, 1.37 mmol) and finely ground NaBH(OAc)₃ (0.15 g, 0.69mmol). The reaction was stirred 16 hours at rt, then heated to 60° C.and stirred 2 hours. Additional NaBH(OAc)₃ (0.08 g, 0.35 mmol) was addedand the reaction stirred at 60° C. for 16 hours, then stirred at rt for6 days. The reaction was quenched with H₂O and extracted with CH₂Cl₂(2×) and EtOAc (1×), dried over MgSO₄, filtered and concentrated. Thecrude product was purified by radial chromatography on silical gel(gradient EtOAc/Hexane 20%–85%), then crystallized inCH₂Cl₂/ether/hexane to give the title compound as fine, off-whitecrystals: ES-MS 437.2 (M+1), ¹H NMR (CDCl₃): δ 8.12 (ap d, J=8.3 Hz,2H), 7.94 (ap d, J=8.4 Hz, 2), 7.29–7.25 (m, 2H), 6.95 (ap t, J=7.4 Hz,1H), 6.90 (ap d, J=8.3 Hz, 2H), 6.57 (s, 1H), 4.23 (t, J=6.0 Hz, 2H),4.09 (s, 2H), 3.71 (s, 2H), 3.08 (t, J=6.0 Hz, 2H), 2.38 (s, 6H). Anal.calcd. for C₂₃H₂₄N₄O₃S: C, 63.28; H, 5.54; N, 12.83; O, 11.00; S, 7.35.Found: C, 62.95; H, 5.49; N, 12.70, O, 11.20; S, 7.60.

Example 301 Preparation of3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenal

a) 4-(1-Hydroxy-allyl)-benzoic acid methyl ester

To a solution of 4-Formyl-benzoic acid methyl ester (Aldrich) (15.0 g,91.40 mM) in 300 mL of THF at −78° C. was added vinyl Grignard(Aldrich)(95.94 mL of a 1.0 molar solution in THF, 95.94 mM) dropwisevia an addition funnel. The mixture was stirred at −78° C. for 3 h thenwarmed to RT and stirred for 18 h. The excess Grignard was quenched with100 mL of sat NH₄Cl and diluted with 300 mL of methylene chloride andextracted three times with methylene chloride, one time with ethylacetate and the combined organics were dried over MgSO₄. The materialwas filtered through paper and concentrated to a yellow liquid. Thematerial was applied to a 65 mm Biotage flash columb and eluted with agradient of 1 L hexanes, 2 L 10% EtOAc in hexanes, 3 L 20% EtOAc inhexanes and 2 L 30% EtOAc in hexanes which upon concentrating provided9.72 g of the 4-(1-Hydroxy-allyl)-benzoic acid methyl ester as a yellowliquid. ¹H NMR (CDCl₃, 300 MHz): δ 8.10 (d, 2H, J=8.1 Hz), 7.54 (d, 2H,J=8.1 Hz), 6.11 (ddd, 1H, J=18.0, 9.0, 6.6 Hz), 5.29–5.50 (m, 2H), 4.01(s, 3H), 2.40 (s, 1H). TLC (50% EtOAC/50% Hexanes) R_(f) 0.49.

b) 4-(1-Acetoxy-allyl)-benzoic acid methyl ester

To a solution of 4-(1-Hydroxy-allyl)-benzoic acid methyl ester (2.3 g,11.9 mM) in 36 m L of CH₂Cl₂ at rt was added pyridine (6 mL, 74 mmol),acetic anhydride (Aldrich)(3 mL, 32.0 mM) dropwise via a syringe andN,N-Dimethyl amino pyridine (20 mg, 0.16 mmol). The mixture was stirredat rt for 18 h. The material was diluted with 100 mL of methylenechloride and extracted three times with methylene chloride, one timewith ethyl acetate and the combined organics were dried over MgSO₄. Thematerial was filtered through paper and concentrated to a yellow liquid.The material was applied to a 40 mm Biotage flash column and eluted witha gradient of 1 L hexanes, 1 L 10% EtOAc in hexanes, 2 L 20% EtOAc inhexanes and 1 L 30% EtOAc in hexanes which upon concentrating provided2.7 g of the 4-(1-Acetoxy-allyl)-benzoic acid methyl ester as a yellowliquid. ¹H NMR (CDCl₃, 300 MHz): δ 8.03 (d, 2H, J=8.0 Hz), 7.42 (d, 2H,J=8.0 Hz), 6.32 (d, 1H, J=6.8 Hz), 6.0 (ddd, 1H, J=15.6, 8.3, 5.9 Hz),5.25–5.38 (m, 2H), 5.95 (s, 3H), 2.37 (s, 3). TLC (50% EtOAC/50%Hexanes) R_(f) 0.60.

c) 4-(1-Acetoxy-allyl)-benzoic acid methyl ester

A solution of 4-(1-Hydroxy-allyl)-benzoic acid methyl ester (11.83 g,50.73 mM) in THF (150 mL) was treated withBis(benzonitrile)dichloropalladium(II) (329 mg, 1.26 mM) at roomtemperature and stirred for 19 h. The material was poured through a plugof Celite 2 cm and silica 2 cm., concentrated and the crude yellowliquid solid was used directly (12 g).

1H NMR (CDCl₃, 300 MHz): δ 8.02 (d, 2H, J=7.2 Hz), 7.46 (d, 2H, J=7.2Hz), 6.70 (d, 1H, J=15 Hz), 6.41 (dt, 1H, J=15, 7.0 Hz), 4.78 (dd, 2H,J=6.8, 0.5 Hz), 3.93 (s, 3H), 2.14 (s, 3H). TLC (50% EtOAC/50% Hexanes)R_(f) 0.60.

d) 4-(3-Hydroxy-propenyl)-benzoic acid methyl ester

To a solution of 4-(3-acetoxy-propenyl)-benzoic acid methyl ester (6.85g, 20.5 mmol) in MeOH was added p-toluenesulfonic acid monohydrate (0.55g, 2.92 mmol). The mixture was stirred at 60° C. for 16 hours,concentrated on the Rotovap, neutralized with sat aq. NaHCO₃, andextracted with EtOAc (3×). The combined organics were washed with brine,dried over MgSO₄, and the solvent removed under vacuum to give a whiteresidue as crude (5.34 g).

ES-MS 193.1 (M+1), ¹H NMR (CDCl₃): δ 7.98 (ap d, J=8.4 Hz, 2H), 7.44 (apd, J=8.4 Hz, 2H), 6.67 (ap d, J=15.9 Hz, 1H), 6.48 (dt, J=15.9, 5.9 Hz,1H), 4.37 (t, J=5.1 Hz, 2H), 3.91 (s, 3H), 1.52 (ap t, 1H).

e) 4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acid methylester

To a solution of 4-(3-hydroxy-propenyl)-benzoic acid methyl ester (5.85g, 30.44 mmol) in DMF (60 mL) was added imidazole (4.14 g, 60.9 mmol)and t-butyl-chlorodiphenylsilane (8.7 mL, 33.5 mmol). The mixture wasstirred at rt for 1 hour and poured into 80% sat. aq. NH₄Cl (60 mL) andextracted with ether (3×). The combined organics were dried over MgSO₄,filtered and concentrated under vacuuum. The product was azeotroped withxylenes on the Rotovap to remove residual DMF, giving the title compound(14.76 g) as crude, which was used in the next step without furtherpurification: ¹H NMR (CDCl₃): δ 7.98 (ap d, J=8.4 Hz, 2H), 7.73–7.69 (m,4H), 7.44–7.36 (m, 8H), 6.71 (ap d, J=16.0 Hz, 1H), 6.39 (dt J=16.0, 4.5Hz, 1H), 4.40 (dd, J=4.5, 1.9 Hz, 2H), 3.92 (s, 3H), 1.11 (s, 9H); TLC(30% EtOAc/Hexane) Rf 0.56.

f) 4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acid

4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acid methylester (17.49 g, 40.6 mmol) was diluted with ethanol (50 mL) and stirredfor 10 minutes, then treated with 1.7 N NaOH (60 mL) and stirred at 45°C. for 4 hours, then 50° C. for 30 minutes. The mixture wasconcentrated, neutralized with 5 N HCl to pH 7 and 1 N HCl to pH 3, andextracted with EtOAc (3×). The combined organics were washed with brine,dried over MgSO₄, filtered and concentrated. The resulting crude wascrystallized in MeOH/CH₂Cl₂/ether/hexane to remove desilylatedbyproduct. The supernatant was concentrated and purified by flashchromatography on silica gel (gradient EtOAc/hexane 10%–100%) to givethe title compound (9.52 g): ¹H NMR (CDCl₃): δ 8.06 (ap d, J=8.4 Hz,2H), 7.71 (m, 4H), 7.47–7.37 (m, 8H), 6.73 (ap d, J=15.9 Hz, 1H), 6.42(dt, J=15.9, 4.6 Hz, 1H), 4.41 (dd, J=4.6, 1.8 Hz, 2H), 1.11 (s, 9H).

g) 4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acidhydrazide

A solution of 4-[3-(tert-butyl-diphenyl-silanyloxy)-propenyl]-benzoicacid (9.52 g, 22.8 mmol) in THF/MeCN 1:1 (100 mL) was treated withN,N′-carbonyldiimidazole (3.89 g, 24.0 mmol) and heated at 60° C. forone hour. After cooling to rt, hydrazine (0.73 mL, 25.0 mmol) was addedby syringe. The mixture was stirred for 1 hour at rt, concentrated,diluted with 75% sat. aq. NH₄Cl, and extracted with EtOAc (3×). Thecombined organics were washed with brine, dried over MgSO₄, filtered,and the solvent removed under vacuum to give the title compound (10.96g) as crude, which was used in the next step without furtherpurification: ¹H NMR (CDCl₃): δ 7.70 (m, 6H), 7.44–7.36 (m, 8H), 7.14(s, 1H), 6.69 (ap d, J=15.9 Hz, 1H), 6.37 (dt, J=15.9, 4.6 Hz, 1H), 4.40(dd, J=4.6, 1.8 Hz, 2H), 1.11 (s, 9H).

h) 4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acidN-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

A solution of (2-phenoxy-ethylsulfanyl)-acetic acid (Maybridge, 4.84 g,22.8 mmol) in THF/MeCN 1:1 (60 mL) was treated withN,N′-carbonyldiimidazole (3.88 g, 23.9 mmol) then heated at 60° C. forone hour. After cooling to rt,4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoic acid hydrazide(10.96 g, 22.8 mmol) was added neat. The mixture was stirred for 2 hoursat rt, concentrated, diluted with 75% sat. aq. NH₄Cl, and extracted withEtOAc (3×). The combined organics were washed with brine, dried overMgSO₄, filtered, and concentrated. The crude oil was purified by flashchromatography on silica gel (gradient EtOAc/Hexane 10%–50%) to give thetitle compound (12.09 g): ES-MS 625.4 (M+1); ¹H NMR (CDCl₃): δ 9.42 (d,J=5.8 Hz, 1H), 8.59 (d, J=5.8 Hz, 1H), 7.70 (m, 6H), 7.44–7.36 (m, 8H),7.29–7.24 (m, 2H), 6.96–6.90 (m, 3H), 6.69 (ap d, J=15.9 Hz, 1H), 6.38(dt, J=15.9, 4.6 Hz, 1H), 4.40 (dd, J=4.7, 1.8 Hz, 2H), 4.26 (t, J=5.9Hz, 2H), 3.51 (s, 2H), 3.10 (t, J=5.9 Hz, 2H), 1.11 (s, 9H).

i)2-{4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-phenyl}-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

To a mixture of 4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-benzoicacid N′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (12.09 g, 19.3mmol) and 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate(5.66 g, 20.3 mmol) in anhydrous CH₂Cl₂ was slowly added DIPEA (7.4 mL,42.6 mmol) by syringe. The mixture was stirred at rt for 72 hours, thenquenched with 80% sat aq. NH₄Cl (120 mL). The organic phase was removedand the aqueous phase extracted with CH₂Cl₂ (1×) and EtOAc (1×). Thecombined organic phases were dried over MgSO₄, filtered andconcentrated. The crude oil was purified by flash chromatography onsilica gel (gradient EtOAc/Hexane 10%–50%) to give the title compound(9.09 g): ES-MS 607.4 (M+1); ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.4 Hz,2H), 7.71 (m, 4H), 7.48–7.37 (m, 8H), 7.30–7.25 (m, 2H), 6.95 (ap t,1H), 6.90 (m, 2H), 6.71 (ap d, J=15.9 Hz, 1H), 6.40 (dt, J=15.9, 4.6 Hz,1H), 4.41 (dd, J 4.7, 1.8 Hz, 2H), 4.22 (t, J=6.2 Hz, 2H), 4.07 (s, 2H),3.07 (t, J=6.2 Hz, 2H), 1.12 (s, 9H).

j)3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-prop-2-en-1-ol

2-{4-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-phenyl}-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole(9.09 g, 15.0 mmol) in anhydrous THF (100 mL) was treated withtetrabutylammonium flouride (1M/THF, 18.7 mL, 18.7 mmol). The reactionwas stirred at rt for 2.5 hours, then poured into water (80 mL). Hexane(25 mL) was added, the organic phase removed, and the aqueous phaseextracted with EtOAc (2×). The combined organics were washed with brine,dried over MgSO₄, filtered and concentrated. The resulting oil waspurified by flash chromatography on silica gel (gradient EtOAc/Hexane10%–60%) to give the title compound (4.25 g) as a white residue: ES-MS369.1 (M+1); ¹H NMR (CDCl₃): δ 7.98 (ap d, J=8.4 Hz, 2H), 7.50 (ap d,J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.97–6.88 (m, 3H), 6.68 (ap d, J=15.9Hz, 1H), 6.50 (dt, J=15.9, 4.6 Hz, 1H), 4.39 (dd, J=5.3, 1.6 Hz, 2H),4.22 (t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.07 (t, J=6.2 Hz, 2H).

k)3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenal

In an oven-dried round-bottom flask, a mixture of anhydrous CH₂Cl₂ (20mL) and oxalyl chloride (2M/CH₂Cl₂, 3.93 mL, 7.86 mmol) was chilled to−78° C. in a dry ice/acetone bath and treated with DMSO (1.50 mL, 21.4mmol) by slow addition with syringe. The mixture was stirred 20 minutesand3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-prop-2-en-1-ol(2.63 g, 7.14 mmol) in CH₂Cl₂ (60 mL) was added slowly by syringe. Themixture was stirred 45 minutes at −78° C. and DIPEA (6.2 mL, 35.7 mmol)was added slowly by syringe. The mixture was stirred an additional 30minutes, removed from bath and stirred 2 hours as it warmed to roomtemperature (rt). The reaction was neutralized with sat. aq. NH₄Cl (75mL) and the organic layer removed. The aqueous phase was extracted withCH₂Cl₂ (1×) and EtOAc (1×), dried over MgSO₄, filtered and concentrated.The crude product was purified by chromatography on silica gel (gradientEtOAc/Hexane 10%–85%) to give the title compound (2.43 g): ES-MS 367.1(M+1); ¹H NMR (CDCl₃): δ 9.76 (d, J=7.7 Hz, 1H), 8.09 (ap d, J=8.4 Hz,2H), 7.69 (ap d, J=8.4 Hz, 2H), 7.51 (d, J=16.0 Hz, 1H), 7.29–7.24 (m,2H), 6.98–6.88 (m, 3H), 6.80 (dd, J=16.0, 7.5 Hz, 1H), 4.23 (t, J=6.1Hz, 2H), 4.09 (s, 2H), 3.08 (t, J=6.1 Hz, 2H).

Example 302Ethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine

To a solution of3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenal(0.282 g, 0.77 mmol) in 1,2-dichloroethane was addedethyl-isopropyl-amine (0.11 mL, 0.92 mmol) and finely ground NaBH(OAc)₃(0.20 g, 0.92 mmol). The reaction was stirred 2 hours at rt, quenchedwith H₂O and the organic phase removed and passed through a Na₂SO₄drying tube. The aqueous phase was extracted with EtOAc (2×), theorganic phases dried in the same manner and the combined organicsconcentrated. The crude product was purified by flash chromatography onsilica gel (gradient EtOAc/Hexane 50%–85%, 2N NH₃ in MeOH/EtOAc 15%),then crystallized in CH₂Cl₂/ether/hexane to give the title compound asfine, white crystals (0.125 g): ES-MS 438.2 (M+1), ¹H NMR (CDCl₃): δ7.96 (ap d, J=8.4 Hz, 2H), 7.48 (ap d, J=8.4 Hz, 2H), 7.29–7.25 (m, 2H),6.98–6.88 (m, 3H), 6.57 (d, J=16.0 Hz, 1H), 6.45–6.37 (m, 1H), 4.22 (t,J=6.2 Hz, 2H), 4.06 (s, 2H), 3.28 (d, J=5.9 Hz, 2H), 3.06 (t, J=6.2 Hz,2H), 2.55 (ap q, 2H), 1.11–1.02 (m, 9H). Anal. calcd. for C₂₃H₂₄N₄O₃S₁:C, 68.62; H, 7.14; N, 9.60. Found: C, 68.44; H, 7.05; N, 9.55.

Example 303Diethyl-(3-{4-[5-(2-phenoxy-elthylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 424.2 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.4 Hz, 2H), 7.48 (apd, J=8.4 Hz, 2H), 7.29–7.25 (m, 2H), 6.97–6.88 (m, 3H), 6.57 (d, J=16.0Hz, 1H), 6.48–6.39 (m, 1H), 4.22 (t, J=6.0 Hz, 2H), 4.06 (s, 2), 3.30(d, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2), 2.61 (q, J=7.1 Hz, 4H), 1.09(t, J=7.1 Hz, 6H). Anal. calcd. for C₂₄H₂₉N₃O₂S: C, 68.05; H, 6.90; N,9.92. Found: C, 67.94; H, 6.88; N, 9.73.

Example 3041-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-piperidine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forEthyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 436.2 (M+1), ¹H NMR (CDCl₃): δ 7.96 (ap d, J=8.4 Hz, 2H), 7.48 (apd, J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.95 (ap t, 1H), 6.90 (ap d, 2H),6.57 (d, J=16.0 Hz, 1H), 6.48–6.41 (m, 1H), 4.22 (t, J=6.1 Hz, 2H), 4.06(s, 2H), 3.17 (d, J=6.1 Hz, 2H), 3.07 (t, J=6.1 Hz, 2H), 2.47 (br s,4H), 1.64 (m, 4H), 1.58 (br s, 2H). Anal. calcd. for C₂₅H₂₉N₃O₂S: C,68.93; H, 6.71; N, 9.65. Found: C, 68.33; H, 6.56; N, 9.42.

Example 305Cyclohexyl-ethyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 478.3 (M+1), ¹H NMR (CDCl₃): δ 7.96 (ap d, J=8.4 Hz, 2H), 7.48 (apd, J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.95 (ap t, 1H), 6.90 (ap d, 2H),6.55 (d, J=16.1 Hz, 1H), 6.41 (m, 1H), 4.22 (t, J=6.1 Hz, 211), 4.06 (s,2H), 3.33 (d, J=5.8 Hz, 2H), 3.07 (t, J=6.1 Hz, 2H), 2.64–2.53 (m, 3H),1.88–1.75 (m, 4H), 1.64 (ap d, J=11.5 Hz, 2H), 1.25 (m, 4H), 1.06 (t,J=7.1 Hz, 3H). Anal. calcd. for C₂₈H₃₅N₃O₂S: C, 70.41; H, 7.39; N, 8.80;Found: C, 69.92; H, 7.32; N, 8.65.

Example 3064-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-morpholine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 438.3 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.2 Hz, 2H), 7.48 (apd, J=8.2 Hz, 2H), 7.29–7.24 (m, 2H), 6.95 (ap t, 1H), 6.89 (ap d, 2H),6.59 (d, J=16.0 Hz, 1H), 6.40 (m, 1H), 4.22 (t, J=6.1 Hz, 2H), 4.06 (s,2H), 3.76 (ap t, J=4.5 Hz, 4H), 3.20 (d, J=6.6 Hz, 2H), 3.07 (t, I=6.2Hz, 211), 2.53 (br s, 4H). Anal. calcd. for C₂₄H₂₇N₃O₃S: C, 65.88; H,6.22; N, 9.60. Found: C, 65.61; H, 6.18; N, 9.56.

Example 307Benzyl-methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-20allyl)-amine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 472.3 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.6 Hz, 2H), 7.48 (apd, J=8.5 Hz, 2H), 7.36–7.31 (m, 4H), 7.29–7.24 (m, 3H), 6.98–6.87 (m,3H), 6.59 (d, J=16.1 Hz, 1H), 6.48–6.40 (m, 1H), 4.22 (t, J=6.2 Hz, 2H),4.06 (s, 2H), 3.58 (br s, 2H), 3.23 (d, J=6.2 Hz, 2H), 3.06 (t, J=6.2Hz, 2H), 2.28 (s, 3H). Anal. calcd. for C₂₈H₂₉N₃O₂S: C, 71.31; H, 6.20;N, 8.91. Found: C, 70.81; H, 6.20; N, 8.75.

Example 3081-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-4-phenyl-piperazine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 513.3 (M+1), ¹H NMR (CDCl₃): δ 7.98 (ap d, J=8.4 Hz, 2H), 7.50 (apd, J=8.4 Hz, 2H), 7.29–7.24 (m, 4H), 6.98–6.84 (m, 6H), 6.62 (d, J=16.0Hz, 1H), 6.45 (m, 1H), 4.22 (t, J=6.2 Hz, 2H), 4.06 (s, 2H), 3.26 (m,6H), 3.07 (t, J=6.2 Hz, 2H), 2.70 (ap t, 4H). Anal. calcd. forC₃₀H₃₂N₄O₂S: C, 70.28; H, 6.29; N, 10.93. Found: C, 70.26; H, 6.28; N,10.92.

Example 3091-Methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-piperazine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)[1,3,4]oxadiazol-2-yl]-phenyl}-propenal using a method similar to thatdescribed forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-215phenyl}-allyl)-amine: ES-MS 451.3 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d,J=8.4 Hz, 2H), 7.47 (ap d, J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.95 (ap t,1H), 6.90 (ap d, 2H), 6.58 (d, J=15.8 Hz, 1H), 6.41 (m, 1H), 4.22 (t,J=6.3 Hz, 2H), 4.06 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 3.07 (t, J=6.2 Hz,2H), 2.54 (br s, 8H), 2.33 (s, 3H). Anal. calcd. for C₂₅H₃₀N₄O₂S: C,66.64; H, 6.71; N, 12.43. Found: C, 66.08; H, 6.71; N, 12.17.

Example 310

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 536.4 (M+1), ¹H NMR (CDCl₃): δ 7.98 (ap d, J=8.5 Hz, 2H), 7.51 (apd, J=8.5 Hz, 2H), 7.39 (d, J=7.0 Hz, 1H), 7.34–7.18 (m, 5H), 6.98–6.85(m, 3H), 6.76 (d, J=5.7 Hz, 1H), 6.63 (d, J=15.8 Hz, 1H), 6.56–6.41 (m,1H), 4.22 (t, J=6.2 Hz, 2H), 4.06 (s, 2H), 3.35 (ap d, 2H), 3.12–3.05(m, 4H), 2.43 (ap t, 2H), 2.25 (ap t, 2H), 1.42 (ap d, 2H). Anal. calcd.for C₃₃H₃₃N₃O₂S: C, 73.99; H, 6.21; N, 7.84. Found: C, 72.89; H, 6.04;N, 7.69.

Example 3111-(3-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-4-phenyl-piperidine-4-carbonitrile

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 537.2 (M+1), ¹H NMR (CDCl₃): δ 7.99 (ap d, J=8.4 Hz, 2H), 7.51 (m,4H), 7.41 (ap t, 2H), 7.35 (ap d, 1H), 7.30–7.24 (m, 2H), 6.95 (ap t,J=7.4 Hz, 1H), 6.90 (ap d, 21), 6.63 (d, J=15.9 Hz, 1H), 6.42 (m, 1H),4.22 (t, J=6.1 Hz, 2H), 4.07 (s, 2H), 3.32 (d, J=6.2 Hz, 2H), 3.13 (d,J=12.1 Hz, 2H), 3.07 (t, J=6.2 Hz, 2H), 2.58 (m, 2H), 2.16 (m, 4H).Anal. calcd. for C₃₂H₃₂N₄O₂S: C, 71.61; H, 6.01; N, 10.44. Found: C,71.10; H, 6.07; N 10.22.

Example 312Cyclopentyl-methyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine

The title compound was synthesized from3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propenalusing a method similar to that described forethyl-isopropyl-(3-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-allyl)-amine:ES-MS 450.3 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.3 Hz, 2H), 7.47 (apd, J=8.3 Hz, 2H), 7.29–7.24 (m, 2H), 6.95 (ap t, 1H), 6.90 (m, 2H), 6.56(d, J=16.1 Hz, 1H), 6.50–6.42 (m, 1H), 4.22 (t, J=6.1 Hz, 2H), 4.06 (s,2H), 3.28 (ap d, 2H), 3.05 (t, J=6.2 Hz, 2H), 2.76 (m, 1H), 2.30 (br s,3H), 1.90 (m, 2H), 1.73 (m, 2H), 1.64–1.43 (m, 4H). Anal. calcd. forC₂₆H₃₁N₃O₂S: C, 69.46; H, 6.95; N, 9.35. Found: C, 69.24; H, 6.83; N,9.25.

Example 313 Preparation of2-[4-(1H-Imidazol-4-yl)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

a)2-(2-Phenoxy-ethylsulfanylmethyl)-5-{4-[4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-phenyl}-[1,3,4]oxadiazole

A solution of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehyde(1.53 g, 4.50 mmol) in anhydrous ethanol (10 mL) was treated withtosylmethyl isocyanide (0.70 g, 5.40 mmol) and KCN (0.30 g, 0.45 mmol)and stirred under N₂ at rt for 1 hour, giving a thick slurry. Themixture was diluted with ether and filtered through paper. Theprecipitate was triturated with ether and filtered again, and theremaining solvent removed under vacuum to give the title compound as anamorphous brown solid:

¹H NMR (CDCl₃): δ 8.06 (ap d, J=8.4 Hz, 2H), 7.85 (ap d, J=8.4 Hz, 2H),7.48 (ap d, J=8.5 Hz, 2H), 7.39 (ap d, J=8.0 Hz, 2H), 7.28–7.23 (m, 3H),6.95–6.87 (m, 3H), 6.12 (d, J=6.2 Hz, 1H), 5.01 (ap d, J=6.2 Hz, 1H),4.21 (t, J=6.0 Hz, 2H), 4.07 (s, 2H), 3.06 (t, J=6.0 Hz, 2H), 2.47 (s,3H).

b)2-[4-(1H-Imidazol-4-yl)-phenyl]-5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazole

In a sealed vial, a solution of2-(2-Phenoxy-ethylsulfanylmethyl)-5-{4-[4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-phenyl}-[1,3,4]oxadiazole(0.405 g, 0.75 mmol) in 7N NH₃/MeOH (5 mL, 35 mmol) was microwaved at100° C. for 15 minutes. The mixture was concentrated, diluted with H₂O,extracted with EtOAc (3×), dried over MgSO₄, filtered and concentrated.The crude product was purified by radial chromatography on silica gel(gradient EtOAc/Hexane 10%–100%; MeOH/EtOAC 10%) to give the titlecompound: ES-MS 379.3 (M+1), ¹H NMR (CDCl₃): δ 8.04 (ap d, J=8.4 Hz,2H), 7.89 (ap d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.46 (s, 1H), 7.29–7.24(m, 2H), 6.97–6.87 (m, 3H), 4.22 (t, J=6.1 Hz, 2H), 4.07 (s, 2H), 3.07(t, J=6.1 Hz, 2H).

Example 314 Preparation of4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehyde

a) 4-Dimethoxymethyl-benzoic acid methyl ester

To a solution of 4-formyl-benzoic acid methyl ester (31.9 g, 194 mmol)in methanol (150 mL) was added p-toluenylsulfonic acid (36.9 g, 194mmol), trimethyl orthoformate (42 mL, 388 mmol), and oven-dried 4 A molsieves (20 g). The mixture was stirred at 70° C. for 16 h, concentratedon the Rotovap, diluted with ether, vacuum filtered through paper andthe filtrate neutralized with sat. aq. NaHCO₃. The organic phase was setaside, the aqueous phase was extracted with EtOAc (2×) and the combinedorganics washed with sat. aq. NaHCO₃, dried over MgSO₄, filtered andconcentrated to give the title compound (21.55 g): ¹H NMR (CDCl₃): δ8.40 (ap d, J=8.4 Hz, 2H), 7.54 (ap d, J=8.1 Hz, 2H), 3.93 (s, 3H), 3.34(s, 6H); TLC (30% EtOAc/Hexane) 0.44.

b) 4-Dimethoxymethyl-benzoic acid hydrazide

To a solution of 4-dimethoxymethyl-benzoic acid methyl ester (21.55 g,102 mmol) in isopropanol (70 mL) under N₂ was added hydrazine (7.5 mL,256 mmol) by syringe. The mixture was stirred at 100° C. for 16 hours,allowed to cool to rt and concentrated on the Rotovap. The crude productwas redissolved in CH₂Cl₂, concentrated, and placed on high vacuum for 4hours to give the title compound (21.37 g): ¹H NMR (DMSO-d₆): δ 9.75 (s,1H), 7.80 (ap d, J=8.4 Hz, 2H), 7.42 (ap d, J=8.4 Hz, 2H), 4.51 (br s,2H), 3.23 (s, 6H); TLC (EtOAc) 0.09.

c) 4-Dimethoxymethyl-benzoic acidNM-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide

A solution of (2-phenoxy-ethylsulfanyl)-acetic acid (23.83 g, 112 mmol)in THF/MeCN 1:1 (100 mL) was treated with N,N′-carbonyldiimidazole(18.20 g, 112 mmol) then heated at 60° C. for one hour. After cooling tort, 4-dimethoxymethyl-benzoic acid hydrazide (23.60 g, 112 mmol) wasadded neat. The mixture was stirred for 2 hours at rt, concentrated,diluted with 65% sat. aq. NaHCO₃, extracted with EtOAc (3×), washed withbrine, dried over MgSO₄, filtered, and the solvent removed under vacuumto give the title compound. This crude product was used in the next stepwithout further purification: ES-MS 387.1 (M+1), ¹H NMR (DMSO-d₆): δ10.47 (s, 1H), 10.13 (s, 1H), 7.88 (ap d, J=8.4 Hz, 2H), 7.48 (ap d,J=8.4 Hz, 2H), 7.29–7.25 (m, 2H), 6.96–6.89 (m, 3H), 4.18 (t, J=6.6 Hz,2H), 3.32 (s, 2H), 3.25 (s, 6H), 3.04 (t, J=6.6 Hz, 2H).

d)4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehyde

A mixture of 4-dimethoxymethyl-benzoic acidN′-[2-(2-phenoxy-ethylsulfanyl)-acetyl]-hydrazide (112 mmol),triphenylphosphine (32.3 g, 123 mmol), and TEA (55 mL, 392 mmol) in THFwas chilled in an ice bath and treated with carbon tetrabromide (40.8 g,331.6 mmol) in 3 portions over 10 minutes. After 30 minutes, thereaction was removed from the bath and stirred 3 hours at rt, thendiluted with EtOAc (200 mL) and 2N HCl (250 mL) and stirred overnight.The mixture was poured into EtOAc (200 mL), shaken, and the organicphase removed. The aqueous phase was extracted with EtOAc (2×) and thecombined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated. The resulting crude was purified by flashchromatography on silica gel (gradient EtOAc/Hexane 10%–100%) to givethe title compound as a white residue (23.92 g): ES-MS 341.0 (M+1), ¹HNMR (CDCl₃): δ 10.09 (s, 1H), 8.21 (ap d, J=8.4 Hz, 2H), 8.01 (ap d,J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.98–6.87 (m, 3H), 4.23 (t, J=6.0 z,2H), 4.11 (s, 2H), 3.08 (t, J=6.0 Hz, 2H).

Example 3154-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine

To a solution of4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehyde(0.533 g, 1.57 mmol) in 1,2-dichloroethane (10 mL) was added morpholine(0.27 mL, 3.13 mmol) and finely ground NaBH(OAc)₃ (0.50 g, 2.35 mmol).The reaction was stirred 2 hours at rt, quenched with H₂O (10 mL) andthe organic phase removed. The aqueous phase was extracted with EtOAc(2×) and the combined organic phases dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel (gradient EtOAc/Hexane 30%–85%) to give the title compound asan amorphous white solid (0.415 g): ES-MS 412.2 (M+1), ¹H NMR (CDCl₃): δ7.99 (ap d, J=8.4 Hz, 2H), 7.47 (ap d, J=8.4 Hz, 2H), 7.29–7.24 (m, 2H),6.95 (ap t, 1H), 6.89 (m, 2H), 4.21 (t, J=6.2 Hz, 2H), 4.06 (s, 2H),3.73 (t, J=4.6 Hz, 4H), 3.57 (s, 2H), 3.06 (t, J=6.2 Hz, 2H), 2.47 (apt, 4H). Anal. calcd. for C₂₂H₂₅N₃O₃S: C, 64.21; H, 6.12; N, 10.21; O,11.66; S, 7.79. Found: C, 64.84; H, 5.86; N, 9.15; O, 11.39; S, 7.99.

Example 3161-Methyl-4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-piperazine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 425.2 (M+1), ¹H NMR (CDCl₃): δ 7.99 (ap d, J=8.3 Hz, 2H), 7.47 (apd, J=8.4 Hz, 2H), 7.30–7.25 (m, 2H), 6.96 (ap t, 1H), 6.90 (m, 2H), 4.22(t, J=6.1 Hz, 2H), 4.07 (s, 2H), 3.59 (s, 2H), 3.07 (t, J=6.1 Hz, 2H),2.52 (br s, 8H), 2.33 (s, 3H). Anal. calcd. for C₂₃H₂₈N₄O₂S: C, 65.07;H, 6.65; N, 13.20. Found: C, 64.23; H, 6.51; N, 12.96.

Example 3171′-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-[1,4′]bipiperidinyl

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 493.2 (M+1), ¹H NMR (CDCl₃): δ 7.97 (ap d, J=8.3 Hz, 2H), 7.45 (apd, J=8.3 Hz, 2H), 7.29–7.24 (m, 2H), 6.97–6.88 (m, 3H), 4.21 (t, J=6.2Hz, 2H), 4.06 (s, 2H), 3.54 (s, 2H), 3.06 (t, J=6.2 Hz, 2H), 2.93 (d,J=11.9 Hz, 2H), 2.53 (br s, 4H), 2.29 (ap t, 1H), 2.00 (ap t, 2H), 1.80(ap d, 2H), 1.68–1.56 (m, 6H), 1.45, (m, 2H). Anal. calcd. forC₂₈H₃₆N₄O₂S: C, 68.26; H, 7.37; N, 11.37. Found: C, 67.68; H, 7.19; N,11.22.

Example 318{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-pyridin-2-yl-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 419.2 (M+1), ¹H NMR (CDCl₃): δ 8.09 (ap d, J=8.4 Hz, 1H), 8.00 (apd, J=8.4 Hz, 2H), 7.51–7.43 (m, 3H), 7.29–7.23 (m, 2H), 6.97–6.87 (m,3H), 6.65 (m, 1H), 6.41 (ap d, J=8.3 Hz, 1H), 4.63 (d, J=6.3 Hz, 2H),4.21 (t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.07 (t, J=6.2 Hz, 2H). Anal.calcd. for C₂₃H₂₂N₄O₂S: C, 66.01; H, 5.30; N, 13.39. Found: C, 65.23; H,5.36; N, 12.71.

Example 319{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-pyridin-2-ylmethyl-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 433.3 (M+1), ¹H NMR (CDCl₃): δ 8.58 (ap d, 1H), 8.00 (ap d, J=8.2Hz, 2H), 7.67 (td, J=7.7, 1.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.33–7.24(m, 3H), 7.20 (m, 1H) 6.97–6.88 (m, 3H), 4.22 (t, J=6.2 Hz, 2H), 4.06(s, 21), 3.99 (s, 2H), 3.97 (s, 2H), 3.07 (t, J=6.2 Hz, 2H).

Example 320{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-pyrimidin-4-ylmethyl-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 420.1 (M+1), ¹H NMR (CDCl₃): δ 8.60 (br s, 1H), 8.20 (br s, 1H),8.00 (ap d, J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.28–7.23 (m, 2H),6.97–6.86 (m, 3H), 6.37 (d, J=5.9 Hz, 1H), 4.66 (d, J=5.9 Hz, 2H), 4.21(t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.06 (t, J=6.2 Hz, 2H).

Example 321{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-pyrazin-2-yl-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 420.1 (M+1), ¹H NMR (CDCl₃): δ 8.01–7.83 (m, 5H), 7.46 (d, J=8.5Hz, 2H), 7.27–7.22 (m, 2H), 6.95–6.86 (m, 3H), 5.12 (ap t, 1H), 4.66 (d,J=5.9 Hz, 2H), 4.21 (t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.06 (t, J=6.2 Hz,2H).

Example 322{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-pyridin-4-ylmethyl-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described for4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 433.3 (M+1), ¹H NMR (CDCl₃): δ 8.57 (dd, J=4.0, 1.5 Hz, 21, 8.01(ap d, J=8.4 Hz, 2H), 7.49 (ap d, J=8.4 Hz, 2H), 7.32–7.24 (m, 4H),6.98–6.88 (m, 3H), 4.22 (t, J=6.1 Hz, 2H), 4.07 (s, 2H), 3.90 (s, 2H),3.85 (s, 2H), 3.07 (t, J=6.1 Hz, 2H).

Example 323{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:ES-MS 439.3 (M+1), ¹H NMR (CDCl₃): δ 7.99 (ap d, J=8.4 Hz, 2H), 7.48 (apd, J=8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.98–6.88 (m, 3H), 4.22 (t, J=6.1Hz, 2H), 4.06 (s, 2H), 3.90 (s, 2H), 3.07 (t, J=6.1 Hz, 2H), 2.85–2.60(m, 6H), 1.83 (m, 6H). Anal. calcd. for C₂₄H₃₀N₄O₂S: C, 65.72; H, 6.89;N, 12.77; 0, 7.30; S, 7.31. Found: C, 65.54; H, 6.91; N, 12.65; O, 7.62;S, 7.31.

Example 3242-(2-Phenoxy-ethylsulfanylmethyl)-5-(4-pyrrolidin-1-ylmethyl-phenyl)-[1,3,4]oxadiazole

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:

Exact Mass 395.17: MS (aspci): m/z=396.2 (M+1); ¹H NMR (CDCl₃, 300 MHz):δ 8.00 (d, 2H, J=7.65 Hz), 7.47 (d, 2H, J=7.60), 6.28 (app t, 2H, J=7.6Hz), 6.86–7.00 (m, 3H), 4.23 (t, 2H, J=6.3 Hz), 4.07 (s, 2H), 3.71 (s,2H), 3.06 (t, 2H, J=6.9 Hz), 2.48–2.62 (m, 4H), 1.75–1.90 (m, 4H). TLC(EtOAc) R_(f) 0.02.

Example 325Diethyl-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-amine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:

Exact Mass 397.18: MS (aspci): m/z=398.2 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ 7.99 (d, 2H, J=7.5 Hz), 7.50 (d, 2H, J=7.5),7.27 (t, 3H, J 37.4 Hz), 6.86–7.00 (m, 4H), 4.22 (t, 2H, 6.0 Hz), 4.07(s, 2H), 3.07 (t, 2H, J=6.6 Hz), 2.57 (q, 4H, J=7.5 Hz), 1.07 (t, 6H,J=7.0 Hz). TLC (EtOAc) R_(f) 0.01.

Example 3261-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-piperidine

The title compound was synthesized from4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzaldehydeusing a method similar to that described4-{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-morpholine:

Exact Mass 409.18: MS (aspci): m/z=410.1 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ 7.90–8.10 (m, 2H), 7.42–7.58 (m, 2H),7.15–7.45 (m, 3H), 6.85–7.00 (m, 4H), 4.22 (t, 2H, J=5.95 Hz), 4.07 (s,2H), 3.55 (b s, 2H), 3.08 (t, 2H, J=6.3 Hz), 2.30–2.49 (m, 4H),1.38–1.70 (m, 6H). TLC (EtOAc) R_(f) 0.02.

Example 327N-{4-[5-(2-Phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide

A mixture of{4-[5-(2-phenoxy-ethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-(2-pyrrolidin-1-yl-ethyl)-amine(0.505 g, 1.14 mmol) and pyridine (1.8 mL, 23 mmol) in CH₂Cl₂ (8 mL) wastreated with acetic anhydride (1.1 mL, 11.4 mmol) and stirred at rtovernight. The mixture was poured into sat. aq. NaHCO₃ and extractedwith EtOAc (3×). The combined organics were dried over MgSO₄, filteredand concentrated. The crude product was purified by radialchromatography (gradient EtOAc/Hexane 20%–100%; 7N NH₃ in MeOH/EtOAc10%–20%) and recrystallized in CH₂Cl₂/ether/hexane to give the titlecompound as a white powder (0.288 g): ES-MS 481.3 (M+1), ¹H NMR (CDCl₃):δ 8.00 (m, 2), 7.39–7.24 (m, 4H), 6.98–6.88 (m, 3H), 4.70 (s, 2H), 4.22(ap t, J=6.1 Hz, 2H), 4.07 (d, J=4.3 Hz, 2H), 3.60–3.40 (m, 2H), 3.02(m, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.51 (ap t, 4H), 2.24, 2.14 (s, 3H),1.85–1.76 (m, 4H). Anal. calcd. for C₂₆H₃₂N₄O₃S: C, 64.97; H, 6.71; N,11.66; 0, 9.99; S, 6.67. Found: C, 65.08; H, 6.75; N, 11.70; O, 9.88; S,6.77.

1. A compound of formula I:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomeror mixture of diastereomers thereof wherein: Ar¹ is a phenyl orbenzofuranyl optionally substituted with one to five groups selectedfrom C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy, C₁–C₈ alkoxy,C₁–C₈ alkylaryl, phenyl, —O-aryl, heteroaryl, cycloalkyl, C₁–C₈alkylcycloalkyl, cyano, —(CH₂)_(n)NR⁶R⁶, C₁–C₈ haloalkyl, C₁–C₈haloalkoxy, halo, (CH₂)COR⁶, (CH₂)_(n)NR⁵SO₂R⁶, —(CH₂)_(n)C(O)NR⁶R⁶,heterocyclic, and C₁–C₈ alkylheterocyclic; wherein the cycloalkyl,phenyl, aryl, and heterocyclic; L¹ is a bond or represented by theformula X₂—(CR³R⁴)_(m)—X₃ where X₂ is attached to Ar¹ and X₃ is attachedto Ar² wherein R³ and R⁴ are independently selected from a bond,hydrogen, C₁–C₈ alkyl, C₂–C₈ alkylene, C₂–C₈ alkynyl, phenyl, aryl,C₁–C₈ alkylaryl; X₂ is independently —CH, —(CR³R⁴)_(m), or O(CR³R4)_(m);X₃ is —S(CR³R⁴)_(m), —O(CR³R⁴)_(m), or —S(CR³R⁴)_(m); Ar² is oxazole;and optionally substituted with one to three substitutents independentlyselected from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, hydroxy, C₁–C₈alkoxy, C₁–C₈ alkylaryl, phenyl, aryl, C₃–C₈ cycloalkyl, C₁–C₈alkylcycloalkyl, cyano, C₁–C₈ haloalkyl, halo, (CH₂)_(n)C(O)R⁶,(CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR⁶R⁶, and C₁–C₈alkylheterocyclic; Ar³ is phenyl optionally substituted with one tothree substituents independently selected from C₁–C₈ alkyl, C₂–C₈alkenyl, C₂–C₈ alkynyl, halo, —NHR⁵, C₁–C₈ haloalkyl, C₃–C₈ cycloalkyl,hydroxy, alkoxy, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO²R⁶,(CH₂)_(n)C(O)NR⁶R⁶, phenyl, C₁–C₈ alkylaryl, and aryl; L² is representedby the formula:X₄—(CR³R⁴)_(m)—X₅; wherein X₄ is attached to Ar³ and is selected fromthe group consisting of —CH, NHCO, NR^(6′)C(O)NR⁶; X₅ is selected fromthe group consisting of —CH₂, —CH₂CH₂—, —CH₂CH₂CH₂—, NR³(CR³R⁴)_(m); Qis a group represented by —NR¹R²; wherein R¹ and R² combine together,and with the nitrogen atom to which they are attached or with 0, 1, 2 or3 atoms adjacent to the nitrogen atom to form a four, five, six or sevenmember nitrogen containing monocyclic heterocycle which may have 1, or 2substituents independently selected from C₁–C₈ alkyl, C₂–C₈ alkenyl,C₃–C₈ cycloalkane, C₁–C₈ alkylaryl, —C(O)C₁–C₈ alkyl, —C(O)OC₁–C₈ alkyl,C₁–C₈ alkylcycloalkane, oxo, halo amino, and (CH₂)_(n)C(O)NR⁶R⁶; R⁵ ishydrogen, CN, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₅–C₈ alkylaryl,(CH₂)_(n)NSO₂C₁–C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,—C(O)C₁–C₈ alkyl, or —C(O)OC₁–C₈ alkyl; and R⁶ and R^(6′) are eachindependently hydrogen, C₁–C₈ alkyl, phenyl, aryl, C₁–C₈alkylaryl, orC₃–C₈cycloalkyl; R⁷ is hydrogen, C₁–C₈ alkyl, phenyl, aryl,C₁–C₈alkylaryl, or C₃–C₈cycloalkyl, and wherein m is an integer from 1to 8; and n is an integer from 0 to
 8. 2. A compound according to claim1 wherein the Ar¹ is benzofuranyl or phenyl; L¹ is —CH₂OCH₂—, or—OCH₂CH₂SCH₂; Ar is oxazole: Ar³ is phenyl; L² is NHCONHCH₂CH₂; and R¹and R² combine with each other and with the nitrogen atom to which theyare attached to form a nitrogen containing monocyclic ring selected fromthe group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl and azepanyl.
 3. A compound according to claim 1 whereinthe group L¹ is a divalent linker selected from the group consisting of:—SCH₂—, —OCH₂—, —CH₂OCH₂—, —OCH₂CH₂OCH₂—, —OCH₂CH₂SCH₂— and—O(CH₂)₃SCH₂.
 4. A compound according to claim 1 wherein the linker L²is: —OCH₂CH₂—, —O(CH₂)₃—, —NHCONHCH₂CH₂—, —NHCON(CH₃)CH₂CH₂—,—NHCON(CH₃)CH₂CH₂CH₂—, or —NHCONHCH₂CH₂CH₂—.
 5. A compound selected fromthe group consisting of:1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-dimethylamino-ethyl)-urea,1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea,1-{4-[2-(Benzofuran-2-ylmethoxymethyl)-oxazol-5-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea,1-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azepane,1-(3-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenoxy}-propyl)-azepane,1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea,1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxazol-5-yl]-phenyl}-3-(3-pyrrolidin-1-yl-propyl)-urea,1-{4-[2-(2-Phenoxy-ethylsulfanylmethyl)-oxalol-5-yl]-phenyl-}-3-(3-pyrrolidin-1-yl-propyl)-urea,and pharmaceutically acceptable salts, solvates, enantiomers,diastereomers or mixture of diastereomers thereof.
 6. The compound ofclaim 1 which is the hydrochloride salt or the bisulfate salt.
 7. Amethod of treating obesity comprising administering to a patient in needthereof a compound of claim
 1. 8. A method of treating Type II Diabetescomprising administering to a patient in need thereof a compound ofclaim
 1. 9. A pharmaceutical formulation comprising a compound of claim1 and a pharmaceutical acceptable carrier for the treatment of obesity.